NZ272142A

NZ272142A - 1,2-disubstituted amine-2-ethyl intermediates

Info

Publication number: NZ272142A
Application number: NZ272142A
Authority: NZ
Inventors: Masayuki Matsukura; Keizo Sato; Naoki Yoneda; Makoto Kaino; Kazutoshi Miyake; Yoshiharu Daiku; Naoya Kishi; Fusayo Yoshida; Kenichi Nomoto; Toshiaki Ogawa; Tadanobu Takamura; Koichi Nose; Mikio Tomimatsu; Masanori Mizuno; Shigeto Negi; Shigeru Souda
Original assignee: Eisai Co Ltd
Priority date: 1993-06-24
Filing date: 1994-06-22
Publication date: 1996-11-26
Also published as: NZ260816A; AU6487894A; AU683460B2; US5606073A; NO942372L; JP3815691B2; US5541213A; FI942923A; CN1111622A; HUT71106A; CA2126020A1; EP0630894A1; NO942372D0; JPH07118237A; KR950000693A; TW278074B; FI942923A0; HU9401917D0

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £72142 $ Priority Date{s):. aabJsa ai.ima 3A1?\^3 Complete Specification F;!ed: Class:(6) j °ub!ication Date: i n 0. Journal No: : Undw the provision* o# Ragat- luton 23 (1) t!h» •— 9p6c!fics£c-n has fci:*n ar.ia-g&eil to aa*..aAc*~ n**- i ■ ii ■ iVi mi ' innV im»/* •V-.J* * V *•" *••• ►. py«" s'^V Ls^ lii'i M Patents Form No. 5 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION Our Ref: JB204259 N.Z. PAT£JTOFFlCE_ 17 WAY 1995 ^HCR!V propenoic acid derivatives and amine intermediates Divisional application out of New Zealand patent application no. 260816 filed 22 June 1994 We, eisai co. ltd., a Japanese company of 6-10, Koishikawa 4- chome, Bunkyo-ku, Tokyo, Japan hereby declare the invention, for which We pray that a patent may be granted to us and the method by which it is to be performed, to be particularly described in and by the following statement: PT0502177 - 1 - (followed by page la) PROPENOIC ACID DERIVATIVES AND AMINE INTERMEDIATES [Field of Industrial Application] The present invention relates to amines, and in particular amines employed as intermediates in the synthesis of propenoic acid derivatives or pharmacologically acceptable salts thereof which are useful as a drug, and particularly as adenosine antagonists. Those propenoic acid derivatives are the subject of New Zealand patent specification no. 260816 from which the present specification is divided. [Background of the Invention and Prior Art] A syndrome having oliguria, anuria, uremia and so forth as the main sign is called acute renal failure, which began to attract attention during the Second World War because it attacked people which had recovered from traumatic shock due to the air raid on London, and has come to the present state. Although there are many causes of acure renal failure, it is believed that such failure is mainly caused by hemorrhage due to injury, surgical operation, aortic rupture or the like; diarrhea due to serious enteritis, infection with Salmonella or cholera, or the like; loss of water and/or electrolyte due to burn, continued vomiting, heat stroke or the like; hemolysis due to incompatible blood transfusion, hemoglobinuria or the like; angiopathy such as renal - icr (followed by page 2) 2721 arterial thrombosis; infectious disease such as pneumonia, sepsis, acute hepatitis, pyelonephritis or candidiasis; allergy; anaphylaxis; influence of a carcinostatic agent such as cisplatin; urethral or ureteral obstruction due to prostatic hypertrophy or malignant tumor; urinary obstruction such as ureteral stone; or the like. Further, a symptom of irreversible decrease in the number of nephrons is called chronic renal failure, and a patient with this failure cannot avoid dialysis with an advance in the symptom, suffering from physical and mental great agony. Additionally, the dialysis of a patient with chronic renal failure generally extends over a long period, so that his expense is also great. Further, it is apparent from the ratio of the number of dialyzers held in Japan to that of the patients necessitating dialysis that the dialyzers must now be worked without intermisission. Therefore, the fact that there are patients with serious acute renal failure who necessitate dialysis temporarily in addition to those with chronic renal failure is significantly problematic. Under these circumstances, the prevention of the symptom of renal failure from reaching a stage necessitating dialysis has become a great issue. - 2 - 272 T 4 However, there has not been found as yet any means which is effective in the prevention of the symptom of chronic renal failure from reaching such a stage, while the regulation of the body fluid which has lost its balance owing to oliguria or anuria by the administration of a diuretic is conducted as the conservative therapy exclusively for the patients with acute renal failure to secure necessary thermal energy. It has been a practice in the prior art to use a loop diuretic such as furosemide or ethacrynic acid against acute renal failure. However, such a diuretic causes an adverse reaction such as hearing loss, worsening of diabetes mellitus or hyperuricemia, so that enough care is needed in the administration thereof. Further, it is needless to say that these drugs are ineffective in protecting the kidney positively to normalize the lowered function thereof, because the drugs serve only as diuretic. Accordingly, it has been expected eagerly to develop a drug which can prevent the worsening of renal failure and which can regulate the body fluid to thereby normalize the function of the kidney. [Summary of the Invention] Under these circumstances, the inventors of the - 3 - 27214? present invention and that described in New Zealand patent specification no. 260 816 have started their studies for the purpose of developing a remedy for renal failure. As a result of the studies, they have directed their attention to adenosine A1 receptors present in the kidney and have found that the above object can be attained by utilizing the antagonism against the A1 receptor. Further, they have made intensive studies on compounds exhibiting such antagonism and have found that the above object can be attained by the propenoic acid derivative which will be described below. The invention of New Zealand patent specification no. 260816, has been accomplished on the basis of this finding. The invention of New Zealand patent specification no. 260816 relates to c propenoic acid derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof, and a remedy for renal failure which comprises the derivative as the active ingredient. R5 B (I) R4 I , wherein A represents an aromatic ring; X, Y and Z each represent carbon, nitrogen, - 4 - 272 1 oxygen or sulfur; R1 represents optically substituted aryl or optionally substituted heteroaryl; R2, R3 and R4 may be the same or different from each other and each represents hydrogen, lower alkyl, lower alkenyl, lower alkynyl or a group represented by formula -W-Q (wherein W represents a group derived from lower alkyl; and Q represents optionally substituted aryl, optionally substituted heteroaryl. cycloalkyl, cyano, hydroxyl, lower alkoxy, acyloxy, carboxyl or a group represented by formula -NR9Ri0 (wherein R9 and R10 may be the same or different from each other and each represents hydrogen, lower alkyl, acyl, carbamoyl or alkylcarbamoyl, or alternatively R9 and Ri0 may represent, together with the nitrogen atom to which they are bonded, a cyclic group); R5 and R6 may be the same or different from each other and each represents hydrogen or lower alkyl; B represents oxygen or sulfur; and R7 and R8 may be the same or different from each other and each represents hydrogen, lower alkyl, lower alkoxy, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, - o - "7 ^ ' L [ optionally protected carboxyalkyl, a group represented by the following general formula: I /R" —c—c< H H R" (wherein Ru represents hydrogen, lower alkyl, optionally substituted aryl, optionally substituted arylalkyl or optionally substituted heteroaryl; R12 represents hydrogen, hydroxyl, lower alkyl, lower alkoxy, optionally protected carboxyl, optionally substituted amino, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl or optionally substituted heteroarylalkyl; and R13 represents hydrogen, hydroxyl, lower alkyl, lower alkoxy, optionally substituted aryl or optionally substituted heteroaryl), or a group represented by formula -V-E [wherein V represents a group represented by formula -CO-, a group represented by formula -(CH2)- or a group represented by the following formula: (CH2)m —R14 —C— H (wherein Rw represents optionally substituted aryl or - 6 - £■» i r c L >- L optionally substituted heteroaryl; and m is an integer of 0 or 1); and E represents optionally substituted aryl or optionally substituted heteroaryl], with the nitrogen atom to which they are bonded, a cyclic group which may be substituted; with the proviso that (1) when one to three of X, Y and Z are nitrogen atoms and one or all of the nitrogen atoms are each bonded to one of the adjacent atoms thereof through a double bond or (2) when one of X, Y and Z Is nitrogen and another of them is oxygen or sulfur, then the corresponding X, Y and/or Z do not have their respective substituents R2, R3 and/or R4 and that at least one of X, Y and Z, is unsubstituted. The invention of New Zealand patent specification no. 260816 provides further use of the compound as defined above or a pharmacologically acceptable salt thereof for manufacturing a preventing or treating agent for a disease against which adenosine antagonism is efficacious. The present invention relates to amines represented by the following formulae: or alternatively, R7 and R8 may represent, together R 19 (IV) - 7 - (followed by page 7a) 272142 wherein R19 and R20 may be the same or different from each other and each represents an optionally substituted aryl, selected from phenyl and naphthyl; an optionally substituted arylalkyl selected from lower alkylphenyl and lower alkylnaphthyl; an optionally substituted heteroaryl selected from pyridyl, furanyl, thienyl, imidazolyl, triazolyl, oxazolyl, pyrazyl, pyrimidyl, pyridazinyl, thiazyl, isoxazolyl, benzimidazolyl, quinolyl, isoquinolyl and benzothiazolyl; or an optionally substituted heteroarylalkyl which is selected from an optionally substituted heteroaryl as defined above being further substituted by lower alkyl, with the proviso that when R19 is 2-, 3- or 4-pyridyl, R20 does not represent phenyl and when R20 is 2-, 3- or 4-pyridyl, R19 does not represent phenyl. In the general formulae (I), and (IV) , the lower alkyl -7a- (followed by page 8) 272142 defined with respect to R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R19, R20 and W refers to linear or branched alkyl having 1 to 6 carbon atoms and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl (amyl), isopentyl, neopentyl, tert-pentyl, 2-methylbutyl, 3- methylbutyl, hexyl, isohexyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1-ethyl-l-methylpropyl and 2-ethyl-3-methylpropyl, among: which methyl and ethyl are preferable. The above lower alkyl may be one substituted with halogen, for example, trifluoromethyl. The lower alkenyl defined with respect to R2, R3 and R4 refers to one derived from the above lower alkyl. The lower alkynyl defined with respect to R2, R3 and R4 refers to one derived from the above lower alkyl. The lower alkoxy defined with respect to R7, R8, R12, R13 and Q refers to one derived from the above lower alkyl. The aryl constituting the optionally substituted aryl as defined with respect to R1, R7, R8, R11, R12, R13, 8 272142 R14, R19, R20, E and. Q refers to phenyl, naphthyl or the like. The heteroaryl constituting the optionally substituted heteroaryl as defined with respect to R*, R2, R3, R4, R7, R8. R11, R12, R13, R14, E and Q includes monocyclic groups such as pyridyl, furanyl, thienyl, imidazolyl, triazolyl, oxazolyl, pyrazyl, pyrimidyl, pyridazinyl, thiazyl and isoxazolyl; and fused heterocyclic groups such as benzimidazolyl, quinolyl, isoquinolyl and benzothiazolyl, among which pyridyl, thienyl, furanyl, quinolyl and benzimidazolyl are preferable. The aryl constituting the optionally substituted arylalkyl as defined with respect to R7, R8, R11 and R12 is as defined above with respect to the optionally substituted aryl. The alkyl constituting it is as defined above with respect to the lower alkyl. The heteroaryl constituting the optionally substituted heteroarylalkyl defined with respect to R7, R8 and R12 is as defined above with respect to the optionally substituted heteroaryl. The alkyl constituting it is as defined above with respect to the above lower alkyl. The acyl defined with respect to R9 and R10 refers to one derived from any carboxylic acid, and examples thereof include those derived from aliphatic saturated n.Z patent office 9 , 15 oct m ~ 9 ■ ! ..... . - 2/21 carboxylic acids, such as formyl, acetyl and propionyl; those derived from aliphatic unsaturated carboxylic acids, such as acryloyl, propioloyl and iaaleo3rl; those derived from carbocyclic carboxylic acids, such as benzoyl, cinnamoyl and toluoyl; and those derived from heterocyclic carboxylic acids, such as furoyl, nicotinoyl and isonicotinoyl, among which formyl and acetyl are preferable. The alkylcarbamoyl defined with respect to R9 and R10 refers to a carbamoyl group to which the above lower alkyl is bonded. The acyloxy defined with respect to Q refers to one derived from the above acyl. The cycloalkyl defined with respect to Q refers to one having 3 to 8 carbon atoms, preferably 5 or 6 carbon atoms. The optionally protected carboxyl defined with respect to R12 includes a free carboxyl group and carboxyl groups protected with lower alkyl groups such as methyl ant ethyl; haloalkyl groups such as 2,2,2-trichloroethyl, 2-iodoethyl and trichloromethyl; lower alkanoyloxyalkyl groups such as pivaloyloxymethyl, 1-acetoxyet.hyl and 2-acetoxyethyl; and heterocyclic groups such as 3-phthalidyl. Further, it also includes various acid amides. In short, the protected - 10 - 7214 2 carboxyl group may be any one which can be cleaved by any means in vivn to form a carboxyl group. The optionally protected carboxyl constituting the optionally protected carboxyalkyl defined with respect to R7 and R8 is as defined with respect to the above optionally protected carboxyl. The pharmacologically acceptable salt according to the present invention includes inorganic acid salts such as hydrochloride, sulfate, hydrobromide, nitrate and phosphate; and organic acid salts such as formate, acetate, trifluoroacetate, maleate, fumarate, tartrate, methanesulfonate, benzenesulfonate and toluenesulfonate. Some of these salts form hydrates and it is needless to say that the present invention includes such hydrates. As will be understood from the chemical structure, seme of the ocnpounds of the present invention may be present as various isomers including geometrical isomers such as cis and trans isomers and optical isomers such as d- and 1-isomers. It is needless to say that the present invention includes all of the isomers. Representative processes for preparing and using the ocnpounds of the present invention and of New Zeciland patent specification no. 260816 will now be ——— - 11 - described. Prpparatl on proregc; i Among the compounds represented by the general formula (I), a compound represented by the following general formula: (wherein R1, R5, R6, R7 and R8 are each as defined above) can be prepared by the following process: 5 H O (Step 1) (v) NNHCONH2 (Step 2) (vi) R5 O R N (Step 3) .CHO R N H COOR14 (Step 4) H (vii) (viii) - 12 - 27?^* wherein R1, R5, R6, R7 and R8 are each as defined above; and R14 represents a carboxyl-protective group. (Step 1) In this step, a compound represented by the general formula (VI) is prepared by reacting a ketone compound represented by the general formula (V) with semicarbazide hydrochloride in the conventional manner. The solvent to be used in this reaction is preferably an aqueous one containing a suitable amount of an alcohol, and the reaction temperature preferably ranges from room temperature to the refluxing temperature of the solvent. (Step 2) In this step, the compound (VI) prepared in the Step 1 is subjected to ring-closure reaction in the conventional manner. Precisely, at least two equivalents of phosphorus oxychloride is dropped into dimethylformamide and - 13 - 279 n A 7 L ii" L* reacted with the compound (VI). The reaction temperature preferably ranges from room temperature to refluxing temperature. (Step 3) In this step, the compound (VII) prepared in the Step 2 is converted into an imidazole derivative represented by the general formula (VIII) through the Wittig reaction. Precisely, the imidazole derivative (VIII) can be prepared by treating a Wittig reagent or a Wittig-Horner-Emmons reagent with a base in an organic solvent and reacting the aldehyde (VII) with the resulting agent. The organic solvent may be any one inert to the reaction and examples thereof include ethers such as tetrahydrofuran and dioxane; and hydrocarbons such as benzene. The base is preferably an alkali metal hydride such as sodium hydride, an alkoxide such as potassium t-butoxide, or an amide such as sodium amide or lithium diisopropylamide. The reaction temperature ranges from 0° C to the refluxing temperature of the solvent. (Step 4) In this step, the propenoic acid derivative (VIII) prepared in the Step 3 is freed from the carboxyl-protective group in the conventional manner. - 14 - 272142 This deblocking can be conducted by hydrolyzing the derivative (VIII) under basic or acidic conditions. When the deblocking is conducted under basic conditions, it is preferably to use sodium hydroxide or potassium hydroxide, while when it is conducted under acidic conditions, it is preferable to use hydrochloric or sulfuric acid. The solvent to be used in the deblocking is preferably a water-containing organic solvent, and the organic solvent may be any one inert to the reaction. The reaction temperature ranges from 0°C to the refluxing temperature of the solvent. (Step 5) In this step, the propenoic acid derivative (IX) prepared in the Step 4 is condensed with an amine (X). The solvent to be used in this reaction may be any one inert to the reaction and examples thereof include tetrahydrofuran, dioxane„ ethyl acetate, benzene, dimethylformamide, dichloromethane, chloroform and acetonitrile. The condensation can be conducted by any conventional method. Examples of the method include-the 1,3-dicyclohexylcarbodiimide (hereinafter abbreviated to "DCC") method, the DCC-[1-hydroxybenzo- 2721 triazole (hereinafter abbreviated to "HOBT") method, the DCC-[N-hydroxysuccinimide (hereinafter abbreviated to "HONSu)] method, and improved methods based on these methods, such as the [l-(3-dimethylaminopropyl)-3-ethylcarbodiimide (hereinafter abbreviated to "EDC1")]-HOBt method. Alternatively, the compound (IX) may be converted into a conventional reactive derivative thereof prior to the condensation with the amine. Examples of the conventional reactive derivative include acid halides prepared by treating the compound (IX) with phosphorus oxychloride or thionyl chloride; mixed acid anhydrides prepared by reacting the compound (IX) with isobutyl chlorofornate (IBCF), l-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline (EEDQ) or ethyl chlorocarbonate; and acid azides prepared from the compound (IX) by the use of diphenyl-phosphoryl azide (DPPA). Further, the compound (IX) may be converted into an active ester such as p-nitrophenylphenyl (-ONp) ester or N-hydroxysuccinimide (-ONSu) ester. The objective compound (XI) can be prepared by reacting such a reactive derivative with the amine (X) in an organic solvent. The reaction temperature ranges from 0°C to the refluxing temperature of the solvent. - 16 - 2721 Preparation propp-^s 2 Among the compounds represented by the general formula (I), a compound represented by the general formula (XII) or (XIII) can be prepared by the following process: r3a (xii) R2a-L or R R3a-L (XV) wherein R1, R5, R6, R7 and R8 are each as defined above; R2a and R3a each represent a group represented by formula -W-Q (wherein W and Q are each as defined above); and L represents a leaving group such as a - 17 - 2721 halogen or p-toluenesulfonyl. Precisely, the objective imidazole derivative represented by the general formula (XII) or (XIII) is prepared by reacting an imidazole compound represented by the general formula (XIV) with a compound represented by the general formula (XV) in the presence of a base. Although the compounds (XII) and (XIII) are generally obtained as a mixture of both, each compound can be isolated by subjecting the mixture to column chromatography. In the compound (XV), L represents a leaving group such as a halogen or p-toluenesulfonyl. The solvent to be used in the reaction may be any organic one inert to the reaction and preferable examples thereof include dimethylformamide, toluene, dioxane and tetrahydrofuran. The base is preferably an alkali metal hydride such as sodium hydride, an alkali metal alkoxide such as potassium t-butoxide or sodium methoxide, or lithium diisopropylamide. The reaction temperature ranges from about -50°C to the refluxing temperature of the solvent. Preparation Process 3 Among the compounds represented by the general formula (I), a compound represented by the general - 18 - formula (XVI): N^N R" R2a/ ^ (xvi) (wherein R1, R23, R5, R6, R7 and R8 are each as defined above) or the general formula (XVII): "vV (xvii) (wherein R1, R^, R®, R7 and R8 are each as defined above; and R4a represents a group represented by-formula -W-Q, wherein W and Q are each as defined above) can be prepared by the following process: - 19 - 27 R (xviii) R5 O 7 R2a-L or R4a-L (XIX is V wherein R1, R2a, R4a, R5, R6, R7 and R8 are each as defined above. Precisely, the objective compound (XVI) or (XVII) is prepared by reacting a compound represented by the general formula (XVIII) with a compound (XIX) in the presence of a base. The solvent to be used in the reaction may be any organic one inert to the reaction and examples thereof include ethers such as tetrahydrofuran and dioxane; hydrocarbons such as toluene; dimethylformamide and acetone. Preferable examples of the base include alkali metal hydrides such as sodium hydride; alkali metal 20 27214 alkoxides such as potassium t-butoxide and sodium methoxide: and lithium diisopropylamide. The reaction temperature preferably ranges from about -50°C to the refluxing temperature of the solvent. Preparation prorssc; A A compound represented by the general formula (I) wherein B is sulfur can be prepared by the following process: wherein R1, R®, R6, R7, R8, X, Y and Z are each as defined above. Precisely, the objective compound (XXI) is prepared by converting a ketone compound represented by the general formula (XX) into the corresponding thioketone compound in the conventional manner. The reagent to be used in the conversion may be any conventional one and examples thereof include Lawson reagent and phosphorus pentasulfide. Y Y (xx) (xxi) - 21 - 27?ik9 '-rm u u The solvent to be used in the reaction may be any organic one inert to the reaction and preferable examples thereof include hydrocarbons such as toluene and benzene; ethers such as dioxane and tetrahydrofuran; and chloroform. The reaction temperature preferably ranges from room temperature to the refluxing temperature of the solvent. Preparation prnrsss 5 Among the compounds represented by the general formula (I), a compound represented by the general formula (XVIII): (wherein R1, R5, R6, R7 and R8 are each as defined above) can also be prepared by the following process: 5 (xv111) - 22 - £ * C i 4 P Knoevenagel reaction, etc. COOH Nv .NH ^ (Step 1) (xxii) (xxiii) NHR7R8(X) *- (Step 3) R? N. N^NH R (xxv) wherein R1, R5, R6, R7 and R8 are each as defined above; and R21 represents a carboxyl-protective group. (Step 1) In this step, a propenoic acid derivative represented by the general formula (XXIII) is prepared from an imidazolylaldehyde represented by the general formula (XXII) through the Wittig reaction. The propenoic acid derivative (XXIII) is prepared by treating a Wittig reagent or a Wittig-Horner-Emmons reagent with a base in a solvent and reacting the aldehyde with the resulting reagent. The solvent may be any organic one inert to the - 23 - 2/214 reaction and examples thereof include ethers such as tetrahydrofuran and dloxane; and hydrocarbons such as benzene. The base may be.any conventional one and preferable examples thereof include alkali metal hydrides such as sodium hydride; alkali metal alkoxides such as potassium t-butoxide; and amides such as sodium amide and lithium diisopropylamide. (Step 2) In this step, the propenoic acid derivative (XXIII) prepared in the Step 1 is hydrolyzed in the conventional manner to remove the carboxyl-protective group. This hydrolysis is conducted under the acidic condition with hydrochloric or sulfuric acid or under the alkaline condition with sodium hydroxide or potassium hydroxide. The solvent to be used in the reaction may be any conventional one inert to the reaction. The reaction temperature ranges from 0°C to the refluxing temperature of the solvent. Alternatively, the propenoic acid derivative represented by the general formula (XXIV) can also be prepared directly from the imidazolylaldehyde (XXII) without the step 2. For example, the compound (XXIV) - 24 - 2/2142 can be prepared by subjecting the compound (XXII) to the Knoevenagel condensation. This condensation is conducted in the presence of a catalytic ainount of an amine and preferable examples thereof include ammonium salts and primary and secondary amines. The solvent to be used in the above condensation may be any organic one inert to the condensation and preferable examples thereof include hydrocarbons such as benzene and toluene. The reaction temperature preferably ranges from room temperature to the refluxing temperature of the solvent. (Step 3) In this step, an objective compound (XXV) is prepared by condensing the propenoic acid derivative (XXIv) prepared in the above Step 2 with an amine represented by the general formula (X). The solvent to be used in this reaction may be any organic one inert to the reaction and examples thereof include ethers such as tetrahydrofuran and dioxane; hydrocarbons such as benzene; dichloromethane, chloroform, acetonitrile and dimethylformamide. All of the conventional condensation methods can be employed in this step, and examples thereof include the DCC method; the DCC-additive methods such as the - 25 - 2/214' DCC-HOBT method and DCC-HONSu method; and improved methods based on these methods, such as the EDC1-H0BT method. Alternatively, the objective compound (XXV) can also be prepared with a reactive derivative of the compound (XXIV). Precisely, the compound (XXV) can also be prepared by converting: the compound (XXIV) into an acid halide by treatment with thionyl chloride or phosphorus oxychloride, into an acid azide by the use of isobutyl chloroformate (IBCF), l-ethoxycarbonyl-2-ethoxy-1,2-dihydroxyquinoline (EEDQ) or chloroazide (DPPA), or into an active ester such as p-nitrophenyl-phenyl (-ONp) ester or N-hydroxysuccinimide (-ONSu) ester, and reacting the reactive derivative thus prepared with the amine (X) in the above organic solvent. Both the former reaction and the latter reaction may be conducted at a temperature ranging from 0°C to the refluxing temperature of the solvent. The processes for preparing representative compounds of the present invention used in the above Preparation processes will now be described. Preparation pronesq A When the amine (X) used in the Preparation - 26 - 2721 process 1 is one represented by the formula (XXVI): HoN j_r« (xxvi) (wherein and R^ each represent a group represented by formula -V-E, wherein V and E are each as defined above) , this amine can be prepared by the following process: £—R 23 LiCH2 N a-picoline derivative (XXYII) such as R22 R22—CHO (xxviii) (Step 1) h o (xxix) (Step 3) H2N (xxvi) wherein R22 and R23 are each as defined above. (Step 1) In this step, an alcohol represented by the general formula (XXIX) is prepared by reacting an a-picoline derivative (XXVII) with an aldehyde represented by the general formula (XXVIII) in the -• 27 - 2721 presence of a base. The base is preferably a strong one such as n-butylllthium. It is preferable that the reaction be conducted at low temperature, still preferably at -78 to -20°C. (Step 2) In this step, a phthalimide derivative represented by the general formula (XXX) is prepared by subjecting the alcohol (XXIX) prepared in the Step 1 to the Mitsunobu reaction. The organic solvent used in this reaction may be any organic one inert to the reaction and preferable examples thereof include tetrahydrofuran, dioxane, chloroform and benzene. This step is conducted by dissolving the alcohol (XXIX) in such an organic solvent and adding triphenylphosphine, phthalimide and diethyl azodlcarboxylate to the obtained solution. The order of addition of these compounds to the solvent may be suitably changed. The reaction temperature may range from -50 to 60°C, preferably from -30°C to room temperature. (Step 3) In this step, the objective amine (XXVI) is prepared by reacting the phthalimide derivative (XXX) prepared in the Step 2 with hydrazine in an alcohol. - 28 - 27? u is-* a u The reaction temperature may range from room temperature to the refluxing temperature of the solvent. Preparation proress B Among the amines (X) used in the Preparation process 1, a compound (XXXIII) represented by formula H2N-NR24-CH2-R25 can also be prepared by the following process: r24 R24—NHNH2 + L-^^R25 b R25 (xxxi) (xxxii) h2n" ^ (xxxiii) wherein R24 and R25 may be the same or different from each other and each represents optionally substituted aryl or optionally substituted heteroaryl; and L represents a leaving group such as a halogen or p-toluenesulfonyl. Precisely, the objective compound (XXXIII) is prepared by reacting a compound represented by the general formula (XXXI) with a compound represented by the general formula (XXXII) in an organic solvent. The organic solvent may be any one inert to the reaction and preferable examples thereof include alcohols such as methanol, ethanol and isopropanol; - 29 - 27 ethers such as dioxane and tetrahydrofuran; hydrocarbons such as toluene, and dimethylformamide. The reaction temperature can be arbitrarily selected within the range of from room temperature to the refluxing temperature of the solvent. Preparatinn prnnftgs C. Among the amines (X) used in the Preparation process 1, a compound (XXXVII) represented by the general formula: E^N-CHR^-Cfy-R27 (wherein R26 and R27 may be the same or different from each other and each represents optionally substituted aryl or optionally substituted heteroaryl) can be prepared by the following process: U (xxxiv) (Step 1) (xxxv) wherein R26 and R27 are each as defined above; and U represents halogen. 30 Precisely, an alcohol (XXXV) is prepared by reacting a halide represented by the general formula (XXXIV) with a suitable metal to form an active derivative and reacting this active derivative with an aldehyde. In particular, any conventional process may be used in the above reaction and examples thereof include the Barbier reaction and the Grignard reaction. According to the Barbier reaction, the alcohol (XXXV) is prepared by reacting the compound (XXXIV) with lithium in a solvent inert to the reaction and thereafter reacting the obtained product with an aldehyde. Preferable examples of the solvent include ethers such as tetrahydrofuran and dioxane; and hydrocarbons such as toluene. Further, desirable results can be attained by conducting ultrasonic irradiation in the stage of preparing the active derivative. According to the Grignard reaction, the alcohol (XXXV) is prepared by reacting the compound (XXXIV) with magnesium in an organic solvent to form an active derivative and reacting this active derivative with an aldehyde. The reaction temperature may be arbitrarily - .31 - 2721 selected between -50°C and the boiling point of the solvent. Prpparatlon process D Among the compounds prepared in the Preparation process A, a chiral compound (XXXX) can be prepared by the following process: (1) H,N N chiral RHN carboxylic (xxvi) acid, derivative thereof, etc. hydrolysis RHN" v (xxxix) N (xxxviii) h2n column chromatography (xxxx) The objective optically active amine (XXXX) is prepared by condensing the racemic compound (XXVI) prepared in the Preparation process A with a chiral carboxylic or sulfonic acid or a derivative thereof to form a diastereomer mixture (XXXVIII), separating the diastereomer mixture (XXXVIII) into chiral compounds (XXXIX) by the conventional column chromatography and hydrolyzing each of the compounds (XXXIX) under acidic - 32 - 27 conditions. The condensation of the compound (XXVI) into the compound (XXXVIII) may be conducted by the conventional method. Examples of the method include the DCC method, the DCC-HOBT method, the DCC-HONSu method, and improved methods based on these methods, such as the EDCl-HOBt method. The solvent to be used in this condensation may be any organic one inert to the reaction and examples thereof include tetrahydrofuran, dioxane, ethyl acetate, benzene, dimethylformamide, dichloromethane, chloroform and acetonitrile. The above reactive derivative includes acid halides, acid anhydrides, acid azides and active esters. The chiral carboxylic acid and derivative thereof include (+)-mandelic acid, (-)-mandelic acid, chiral amino acid derivatives, (+)-tartaric acid, (+)-camphorsulfonic acid, (+)-phenylethanesulfonic acid, (-)-phenylethanesulfonic acid, and derivatives thereof. The hydrolysis of the compound (XXXIX) into the compound (XXXX) is conducted in an aqueous medium under strongly acidic condition with hydrochloric or sulfuric acid, generally at a temperature ranging from - 33 - 2 7-214 room temperature to refluxing one. (2) Alternatively, the optically active compound (XXXX) can also be prepared directly from the racemic compound (XXVI) by frictional crystallization. Precisely, the chiral amine can be prepared by reacting the compound (XXVI) with a chiral carboxylic or sulfonic acid to form a salt mixture, subjecting the mixture to fractional recrystallization repeatedly to conduct purification, and converting the obtained pure salt into an amine. The chiral carboxylic or sulfonic acid used as the resolving agent may be selected from among those described in the above paragraph (1). Examples of the solvent usable in the fractional recrystallization include acetone, methanol, ethanol, isopropanol, water, and mixtures of two or more of them. The reaction temperature may be arbitrarily selected between -20" C and the refluxing temperature of the solvent. Pharmacological Experimental Examples will now be described to illustrate the usefulness of the compounds of New Zealand patent specification no. 260816 iii more detail. - 34 - 27214 [Pharmacological Experimental Example] In this example, (+)-(E)-N-{1-(4-chloropyridin-2-yl)-2-(pyridin-2-yl)ethyl}-3-{3-(3-fluorophenyl)-1H-pyrazol—4-yl}-2—propenamide was as the test oanpound. 1. Activity ag-ainst vnerol-inrinopri r^rial trmihla mnripl (i) Experimental method Fisher 344 male rats aged 8 weeks and weighing 200 to 230 g were kept without water for 18 hours prior to the use. Thereafter, the test compound was orally administered forcedly to the test group of rats in an amount of 0.3 mg/5ml/kg. while a solvent [2% Tween 80 solution] to the control group of rats In an amount of 5 ml/kg. Ai'ter 60 minutes from the administration of the test compound or solvent, a 50% solution of glycerol in physiological saline was intramuscularly administered to each rat through both left and right femoral muscles in an amount of 10 ml of kg. After the completion of the intramuscular administration, the rats were watered. After about 24 hours, the rats were etherized and blood was sampled from each rat. The blood samples thus prepared were each centrifuged to collect serum, which was analyzed - 35 - 27214 for urea nitrogen and creatinine, (ii) Experimental results The results are given in Table 1. [Table 1] Serum urea nitrogen (mg/dl) serum creatinine (mg/dl) Control group 185.4 ± 3.2 4.76 ± 0.21 Test group 142.4 ± 10.5* 3.47 ± 0.30* * P<0.05 (unpaired t-test vs control) 4 2. Activity ayainst nlsplatln-lndncpd fastrlr t.ronhlp modpl (i) Experimental method Cisplatin was subcutaneously administered to Fisher 344 male rats aged 7 weeks and weighing 170 to 200 g in an amount of 6 mg/5 ml/kg. Immediately after the administration, the test compound was orally administered forcedly to the test group of rats in an amount of 1 mg/ 5 ml/kg, while a solvent (2% Tween 80 solution) to the control group of rats in an amount of 5 ml/kg. Six hours after the administration, the administration of the test compound and the solvent to the test group and the control group respectively was conducted in a similar manner to that described above. Thereafter, the same administration was repeated on the next day twice, and on the third and forth days - 36 - each once. On the fifth day, the rats were etherized and blood was sampled from each rat. The blood samples thus prepared were analyzed for serum urea nitrogen and creatinine. (ii) Experimental results The results are given in Table 2. [Table 2] Serum urea nitrogen (mg/dl) serum creatinine (mg/dl) Control group 93.4 ± 6.5 2.15 ± 0.16 Test group 52.9 ± 2.3* 1.49 ± 0.04* * P<0.05 (unpaired t-test vs control) 3. Diuretic activity (1) Experimental method Fisher male rats aged 8 weeks and weighing 190 to 210 g were fasted for 18 hours prior to the use. The test compound was orally administered forcedly to the test group of rats in a state dispersed in a 0.4% solution of Tween 80 in physiological saline in an amount of 1 mg/25 ml/kg, while a 0.4% solution of Tween 80 in physiological saline to the control group of rats in the same amount as that administered to the test group. Immediately after the administration, the rats were put in individual metabolism cages respectively to collect urine from each rat for 2 - 37 - hours. The urinary volume of each rat was determined and thereafter the urine was examined for uric acid concentration to calculate the amount of uric acid egested. The control group was composed of six rats, while the test group three rats. The amounts of uric acid excreted from the rats of each group were averaged out to determine the increment of the excretion of uric acid based on the averages. (ii) Experimental results The urinary volume of the test group was 605% and the amount of uric acid excreted therefrom was 166% when the urinary volume and the amount of the excreted uric acid of the control group are taken each as 100%. 4. Adfrnns 1 ris ant.a g-nrrt sm (i) Experimental method Hartley male guinea pigs weighing 250 to 400 g were beaten to death. The heart was immediately extirpated from each guinea pig and put in the Krebs-Heuseleit solution saturated with a gas mixture comprising 95% of oxygen and 5% of carbon dioxide. Thereafter, the right atrium was extirpated from the heart. The samples thus preparer were each vertically suspended in a Magnus tube (capacity: 6 ml) filled with a nutrient liquid at 37°C and the same gas mixture as that used above was passed through the - 38 - 2721 tube. The change in tension was isometrically determined under a load of about 0.5 g and the spontaneous heart rate was measured and recorded with a cardiotachometer by utilizing the signal of the change as a trigger. After the stabilization of the sample, 10"5 mol of dipyridamole was added to each Magnus tube. Thereafter, the test compound was added directly to each of the Magnus tubes of the test group in a state dissolved in DMSO, while a solvent (DMSO) to each of the Magnus tubes of the control group in the same amount as that added to each Magnus tube of the test group. The resulting Magnus cubes was allowed to stand for 20 minutes. Thereafter, 10"8 to 10"2 mol of adenosine was cumulatively added to each Magnus tube until the spontaneous heart beat discontinued. The EC5Q value with respect to the heart rate lowering effect of adenosine was calculated and the adenosine antagonism was represented b> pA2 value (-log M). (ii) Experimental result pA2 value = 10.41 As described above, the test octnpound exhibits adenosine antagonism and is - 39 - effective in the prevention and treatment of diseases against which this antagonism is efficacious. Specific examples of such diseases include edemas such as hepatic, renal and heart edemas; hypertension; and acute and chronic renal failures. In particular, renal failure, as described in the above pharmacological Experimental Example, can be inhibited from sideration by administering the compound of New Zealand patent specification no. 260816 in advance. In other words, it is apparent that such carpoiSnds are also effective in preventing the above diseases. Further, the cornounds of New Zealand patent specification no. 260816 are less toxic and highly safe, thus being valuable also in this sense. Ihe ocnpounds of New Zealand patent specification no. 260816 may be orall} or parenterally administered as a protective and therapeutic agent for the above diseases. The dose thereof varies depending upon the symptom of a patient and the extent thereof; the age, sex, weight and drug sensitivity of a patient; the method, timing and interval of administration; the kind and properties of the pharmaceutical preparation; the kind of the drug to be administered therewith and so on, and is not particularly limited. For example, when the compound is orally administered, the dose per adult a day is - 40 - 2721 generally about 0.1 to 1000 mg, preferably 0.5 to 500 mg, still preferably 1 to 10 mg, which may be administered in one to several portions, preferably one or two portions a day. When it is administered as an injection, the dose is 0.1 to 100 [ig/kg. Hiese pharmaceutical preparations are prepared by the vise of the conventional carrier in the conventional manner. More precisely, a solid preparation for oral administration according to the present invention is prepared by adding a filler and, if necessary, a binder, disintegrator, lubricant, color and/or corrigent to an active ingredient and shaping the obtained mixture into a tablet, coated tablet, granule, powder or capsule. Examples of the filler include lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose and silicon dioxide; those of the binder include polyvinyl alcohol, polyvinyl ether, ethylcellulose, methylcellulose, acacia, tragacanth, gelatin, shellac, hydroxypropylcellulose, hydroxy-propylmethylcellulose, calcium citrate, dextrin and pectin; those of the lubricant include magnesium stearate, talc, polyethylene glycol, silica and hardened vegetable oil; those of the color include - 41 - those authorized as pharmaceutical additives; and those of the corrigent include cocoa powder, menthol, aromatic powder, mentha oil, borneol and powdered cinnamon bark. Of course, the tablet and granule may be suitably coated with sugar, gelatin or the like, if necessary. An injection according to the present invention is prepared by adding a pH regulator, buffer, stabilizer and/or solubilizing agent to an active ingredient at need and formulating the mixture into an injection for subcutaneous, intramuscular or intravenous administration by the conventional method. [Example] Examples will now be described to facilitate the understanding of the invention of New Zealand patent specification no. 260816, although that invention is not limited to them. Further, Preparative Examples will be described prior to the Examples to describe the preparation of the compounds of the present invention, although the present invention is not limited to these preparation examples. These compounds may be used for preparing the compounds of New Zealand patent specification no. 260816. Preparative Example 1 3-Fluormacetophenone semicarbazone - 42 - 27 N—NHCONH2 500 ml of an aqueous solution of 66.9 g of sodium acetate and 49.9 g of seniicarbazide hydrochloride were added to 50 ml of an ethanolic solution of 51.2 g of 3-fluoroacetophenone. The obtained mixture was heated under reflux for 3 hours to precipitate crystals. which were recovered by filtration. Yield: 72.3 g. • m.p.: 205-207°C • %-NMR (DMS0-d6) 5 (ppm) 2.16(3H, s) 6.58(2H. br-s) 7.12(1H, dt, J=8Hz, 1Hz) 7.37(1H, dd, J=8Hz, 8Hz) 7.61(1H, d, J=8Hz) 7.50(1H, dt, J=8Hz, 1Hz) 9.39(1H, s) Prsparatlvft Examples ?. and 3 The following compounds were prepared in a similar manner to that of the Preparative Example 1. Preparative Example 2 2-Ar»ptv1 -S-met.hvl thl ophp.ng spmi oarhayorie - 43 - 272 ^T3ks,/cH3 H3c/xs/y N—NHCONH2 • m. p . : 215-218® C • ^H-NMR (DMSO-d6) 5 (ppm) 2.15(3H, s) 6.24(2H, br-s) 6.73(1H. d, J=3Hz) 7.15(1H, d. J=3Hz) 9 . 35(1H, s) Prftparative Fyampla 3 2-Acetyl-S-chlnrnthi nphpne qpm1narha7nnp c^Qv- N—NHCONH2 • iH-NMR (DMSO-dg) 6 (ppm) 2.16(3H, s) 6.32(2H, br-s) 7.04(1H, d, J=4Hz) 7.21(1H, d. J=4Hz) 9.49(1H, s) PrRDaratlvp Fvamplft 4 3- ( 3-F"hirnrphftnv1 ) -1 TT-4-pyray.nl snarhal dphvdp - 44 - The synthesis of the title compound was conducted by the use of the 3-fluoroacetophenone prepared in the Preparative Example 1 according to the process described in J. Heterocyclic Chem., X, 25 (1970), and the obtained crude product was recrystallized from ethanol/water. Yield: 48.5 g. • m.p.: 132-134° C • !H-NMR (CDC13) 5 (ppm) 7.25-7.32(1H, ra) 7.42-7.52(m, 3H) 8.18(1H, s) 10.00(1H, s) Preparative Framples 5 arid R The following compounds were prepared in a similar manner to that the Preparative Example 4. Fyample 5 3- r 5-Methvl thi npheri-2-vl ) -1 H-4-pvra7:ol e-oarhalriehvrie - 45 - 2721*5 9 1=3 - £=a H The title compound was prepared in a similar manner to that of the Preparative Example 4. • m.p.: 97-99° C • te-NMR (CDClg) 6 (ppm) 2.54(3H, s) 6.81(1H, d, J=4Hz) 7.54(1H, d, J=4Hz) 8.13(1H, s) 10.06(1H, s) Prsparatlvfi Fyampl e R 3- ( S-P.hl orothi r>phen-2-vl )-1H-4-pvra7.o1fi-ca rha 1 riehvrie- H • ^H-NMR (CDClj) 6 (ppm) 6.95(1H, d, J=4Hz) 7.74(1H, d, J=4Hz) 8.17(1H, s) 10.03(1H, s) Preparative Kvampls 7 Fthvl (F)-(3-phenvl-1H-pvra?nl-4-vl^-2-propenoate - 46 - 2 COOC2Hs H 180 ml of a solution of 49-3 g of ethyl diethylphosphonoacetate in tetrahydrofuran was dropped into 30 ml of a suspension of 8.8 g of 60% sodium hydride in tetrahydrofuran under cooling with ice. The obtained mixture was stirred for 30 minutes, followed by the addition thereto of 250 ml of a solution of 34.4 g of 3-phenyl-lH-pyrazole-4-carbaldehyde in tetrahydrofuran under cooling with ice. The resulting mixture was stirred at room temperature for 12 hours, treated with an aqueous ■ solution of ammonium chloride, and extracted with ethyl acetate. The organic phase was dried and concentrated. The residue was recrystallized from isopropyl ether/n-hexane. Yield: 36.3 g. • m.p. : 91-94° C • !H-NMR (CDClg) 6 (ppm) 1.31C3H, t, J=7Hz) 4.23(2H, q, J=7Hz) 6.26(1H, d, J=16Hz) 7.43-7.55(5H, m) 7.67(1H, d, J=7Hz) 7.85(1H, s) - 47 - 272 1 Prep^ratlvp Fyampl PS R to 11 The following compounds were each prepared in a similar manner tc that of the Preparative Example 7. Preparative Fxampl s 8 Fthvl (FW3- (3-fl norophenvl ^-1 H-pvra7.nl -4-vl 1-2- H • m. p . : 106-108" C • XH-NMR (CDCI3) 8 (ppm) 1.32(3H, t, J=7Hz) 4.24(2H, q, J=7Hz) 6.27(1H, d, J=16Hz) 7.15(1H, m) 7.11-7.32(2H, m) 7.45(1H, m) 7.66(1H, d, J=16Hz) 7.88(1H, s) Rrepflrat1-Yf. Example, 3 Fthvl (F.) -(3- (S-mgthvl thi ophpn-9-vl 1-1 W-pvra7:ol -4-vl \-?-proppnr>atp • ^-NMR (CDC13) 6 (ppm) - 48 - 2721 1.32(3H, t. J = 7Hz) 2.53(3H, s) 4.25(2H, d, J=7Hz) 6.26(1H, d, J=16Hz) 6.79(1H, d, J=4Hz) 7.0 8(1H, d, J=4Hz) 7.80(1H, d, J=16Hz) 7.85(1H, s) Prpparati ve Fxamplp 10 Fthvl (4") -2-methyl -■f3-fn-mpt.hv1-fnran-9-v1')-1H-pvra7n1 -4-vl )-?-propenoate • ^-NMR (CDClg) 5 (ppm) .1. 36 (3H, t, J = 7Hz) 2 .14 (3H, s) 2.39(3H, s) 4.27(2H, q. J=7Hz) 6.13(1H, d, J=3Hz) 6.59(1H, d, J=3Hz) 7.27(1H, s) 7.83(1H, s) Preparative Fxarnple 11 Fthvl f F1 -3- 1 3- f Fj-rrhl nrot.hl rvphen-P.-vl > -1 H-pvraznl-4-vlI-S-propenoate N' H H - 49 - • 272142 . • ]H-NMR (CDClo) 6 (ppm) J 1.33(3H, t. J=7Hz) 4.26(2H, q. J=7Hz) 6.28(1H, d. J=15Hz) 6.96(1H, d, J=4Hz) 7.07(1H, d, J=4Hz) 7.73(1H, d, J=15Hz) 7.87(1H, s) | Prpparativp Fvamplp 19 (F1 - ( 3-Phenvl -1H-pvra7.o1 -4-vl ) - 2-T>rot>enoi r. add COOH 200 ml of ethanol and 180 ml of a 10% aqueous solution of sodium hydroxide were added to 35.7 g of the ethyl (E)-(3-phenyl-lH-pyrazol-4-yl)-2-propenoate prepared in the Preparative Example 7. The obtained mixture was heated under reflux for 1.5 hours and concentrated to about two-thirds of the initial volume. The concentrate was neutralized with 3N hydrochloric acid to precipitate crystals, which were recovered by filtration. Yield: 31.3 g. • m.p. : 263° C (dec.) * ^-NMR (DMSO-dg) 6 (ppm) 6.32 (1H, d, J=16Hz) 7.46-7.58(5H, m) 7.49(1H, d, J=16Hz) 8.26(1H, bs) - 50 - 2 7 Prpparative Fvsinplpq 13 to 1R The following compounds were each prepared in a similar manner to that of the Preparative Example 12. Prsparativp Frstnplp 13 fF) -13- (3-F1 liorophpnvl ) -1 H-pvra7.o1 -4-vl \-2-proppnnlo arid COOH • m.p.: 281°C (approx. dec.) • ^-NMR (DMSO-d8) 5 (ppm) 6.33(1H, d, J=16Hz) 7.26-7.39(3H. m) 7.49(1H, d, J=16Hz) 7.59(1H, m) 8.33(1H, br-s) This compound could also be prepared by the following process. A liquid mixture comprising 3-(3-fluorophenyl)-lH-pyrazole-4-carbaldehyde (2 g, 10.5 mmol), ethyl diethylphosphonoacetate (3.25 g, 14.5 mmol), a methanolic solution of sodium methylate (28%, 2.6 g, 12.0 mmol) and tetrahydrofuran (20 ml) was stirred in a 50-ml flask at room temperature for 24 hours to complete a reaction. 50 ml of a IN aqueous solution 42 -51 - of caustic soda was added to the reaction mixture. The obtained mixture was stirred for 36 hours and neutralized with a IN aqueous solution of hydrochloric acid. Water (50 ml) was added to the resulting mixture to form precipitates, which were recovered by filtration, washed with water, well dried, and added to acetone (15 ml). The obtained mixture was stirred for one hour, followed by the addition thereto of isopropyl ether (15 ml). The crystals thus precipitated were recovered by filtration. 1.89 g of the title compound was obtained (yield: 79%). Preparative Fxamplp 14 (Ft-J 3-(R-Msthvl th1ophpn-3-vl 1-1H-pvra?nl-4-vl\-2-proppnr>1 c. H • m.p.: 228°C (approx. dec.) • ^-NMR (DMS0-d6) 6 (ppm) 2.50(3H, s) 6.33(1H, d, J=16Hz) 6.90(1H, br-s) 7.12(1H, br-s) 7.64(1H, d, J=16Hz) 8.27(1H, br-s) Preparativp F.yanvpl p IS - 52 - *^rr 9 ■ 9 + (Ft -?-IVTpthv1 - 13-( 5-mpf.hvl -fnran-^-vl 1 -1 H-pvrazol -4-vn-2-propenr1 n add • m.p.: 215-218"C • %-NMR (DMSO-d6) 5 (ppm) 2.02(3H, s) 2.35(3H, s) 6.26(1H. d, J = 3Hz) 6.57(1H, d, J=3Hz) 7.79(1H, s) 8.01(1H, br-s) Prpparat.lvs Fxamule 16 (P.\5-C.hl oroth 1 ophp.n-9-vl t -1H-pvra7.nl -4-vl \-9-proppnni c add • XH-NMR (DMSO-d6) 5 (ppm) 6.37(1H, d, J=16Hz) 7.18(1H, d, J=4Hz) 7.21(1H, d, J=4Hz) 7.60(1H, d, J=16Hz) 8.39(lH, s) Prpparatlvs Fxamplp 17 n - (4-P.hl oropvrl di n-2-vl )-2-fpvr1 din-2-vl ) >pt.hv1 a 1nnhnl H y .COOH H - 53 - 2721 Cl 21.1 g of a-picoline was dissolved in 500 ml of tetrahydrofuran and the obtained solution was cooled to -60 to -55°C. 99.6 ml of a 2.5 M solution of n-butyllithium in haxane was dropped into the resulting solution in such a way that the bulk temperature did not exceed -55°C. After the completion of the dropping, the obtained mixture was stirred for 20 minutes. A solution of 32.0 g of 4-chloro-2-pyridinecarbaldehyde in tetrahydrofuran was dropped into the resulting mixture in such a way that the bulk temperature did not exceed -55°C. The cooling bath was taken off and the mixture was stirred for 20 minutes, followed by the addition thereto of water. The resulting mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulfate and distilled in a vacuum to remove the solvent. The residue was purified by silica gel column chromatography (with an ethyl acetate/hexane (2 : l) mixture) to give 21.9 g of the title compound - 54 - 272142 as an oil. • NMR (CDCI3) 8 (ppm) 3.13(1H, dd, J=9Hz 15 Hz) 3.39(1H, dd, J=3Hz, 15Hz) 5.20(1H, dd. J=3Hz, 9Hz) 6.34(1H, br-s) 7.15-7.21(3H, m) 8.44(1H, d. J=6Hz) 8.52(1H, ddd, J=l, 2. 5Hz) Prpparativs Fxamplp IS 1 - ( 3-r.hl orophpnvl 1 M -tr f php.nvl msthvl -i mi -2-vl 1 pt.hvl alcohol The title compound was prepared in a similar manner to that of the Preparative Example 17. • %-NMR (CDClg) 8 (ppm) 2.20(1H, dd. J=3Hz, 16Hz) 2.28(1H, dd, J=10Hz, 16Hz) 4.20(1H. dd, J=3Hz, 10Hz) 6.73(1H. d, J=2Hz) 6.82-6.85(2H, m) 6.98(1H, d, J=2Hz) 7.06-7.10(8H, m) 7.30-7.35(9H, m) Preparativp Fxample 19 N OH 55 2721 1 - ( 3-Ch 1 orophpnvl 1 -2-f pvrl d 1n-?-v1 ) Pthvl al r^ohnl 50 ml of a solution of 5.58 g of 2-picoline in tetrahydrofuran was cooled to -65°C, followed by the dropwise addition thereto of 26.4 ml of a 2.5 M solution of n-butyllithium in hexane. The obtained mixture was stirred at a bulk temperature of -50 to -30°C for 30 minutes, followed by the dropwise addition thereto of 50 ml of a tetrahydrofuran solution of 8.85 g of 3-chlorobenzaldehyde at -50°C. The temperature of the obtained mixture was raised to 0°C. The resulting- mixture was cooled, treated with an aqueous solution of ammonium chloride, and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and concentrated (yield: 13.5 g). This concentrate was used in the subsequent step without purification. • ^-NMR (CDC13) 5 (ppm) 3 .11(3H, d, J=6Hz) 5.15(2H, t, J=6Hz) 7.11(1H, d, J=8Hz) 7.17-7.33 (m, 4H) 7.44(1H, d, J=2Hz) 7 . 64(1H , in) 8 . 54(1H , d. J = 5Hz) 56 27 Prpparat.ivp Fvaroplp 20 1 - ( fi-f.hl nrnpvrl riin-g-v'n-2-f pvrl Hi n-9-vl ) pthvl alcohol 50.2 g of 2-picoline was dissolved in 1363 ml of tetrahydrofuran and 237.2 ml of a 2.5 M solution of n-butyllithium in hexane was added to the obtained solution at -50°C in a nitrogen stream. The obtained mixture was stirred at that temperature for 50 minutes, followed by the addition thereto of a solution of 76.2 g of 6-chloro-2-pyridinecarbaldehyde in 1363 ml of tetrahydrofuran at -50°C. The obtained mixture was stirred at that temperature for 30 minutes and brought to 0°C at room temperature. Water was added to the resulting mixture to terminate the reaction. Ethyl acetate and water were added to the obtained mixture to conduct extraction. The ethyl acetate phase was washed with a saturated aqueous solution of common salt, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (with a hexane/ethyl - 57 - 272142 acetate (2 : 1) mixture) to give 38.7 g of the title compound. • te-NMR (CDClg) 6 (ppm) 3.12 (1H, dd, J=9Hz, 15H?:) 3.40(1H, dd, J=3Hz, 15Hz) 5.19(1H, dd. J=3Hz, 9Hz) 6.37(1H, br-s) 7.15-7.20(3H, m) 7.51-7.66(3H, m) 8.50(1H, ddd, J=lHz, 2Hz, 5Hz) Prpparatlvp Fvamplp 21 N- T -f 1 - (4-nhl nrnpvrl H1n-2-vl )-2-( pvrl d1n-9-vl1ypthvl"Inhthali ml da 21.9 g of {1-(4-chloropyridin-2-yl)-2-(pyridin-2-yl)}ethyl alcohol, 27.1 g of triphenylphosphine and 15.2 g of phthalimide were dissolved in 200 ml of tetrahydrofuran. The obtained solution was cooled to -20°C, followed by the dropwise addition thereto of a tetrahydrofuran solution of 18.0 g of diethyl azodlcarboxylate. After the completion of the CI 58 2721 dropwise addition, the mixture was brought to room temperature and stirred for 20 minutes. Aqueous hydrochloric acid was added to the resulting mixture and the obtained mixture was washed with ethyl acetate, followed by the neutralization, of the aqueous hydrochloric acid with sodium hydrogen-carbonate. The resulting mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulfate and heated to distill away the solvent. The residue was purified by silica gel chromatography (with a hexane/ethyl acetate (3 : 1 to 1 : 1) mixture) to give 23.4 g of the title compound as a crystal (yield: 68.8 %). Preparative Fxainpl f>. 22 N- { 1 - (S-C.hl orophenvl ^ -2- (Pvr1 r11 n-?.-vl ) pthvl \ -phthal1 mlrie 70 ml of a solution of 16.5 g of triphenyl-phosphine in tetrahydrofuran was cooled to -50°C, CI M !■ ii# - 59 - 2721 followed by the gradual dropwise addition thereto of 40 ml of a solution of 11.0 g of diethyl azodlcarboxylate in tetrahydrofuran. The obtained mixture was stirred at -30°C for 30 minutes, followed by the dropwise addition thereto of 50 ml of a tetrahydrofuran solution of 13.4 g of the l-(3-chlorophenyl)-2-(pyridin-2-yl)ethyl alcohol prepared in the Preparative Example 19. The obtained mixture was stirred at that temperature for 30 minutes, followed by the addition thereto of 9.28 g of phthalimide. The obtained mixture was stirred at room temperature for 30 minutes and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to column chromatography and eluted with a toluene/ethyl acetate mixture. Yield: 12.9 g. • ^-NMR (CDC13) 6 (ppm) 3.64(1H, dd, J=6Hz, 14Hz) 4.14(1H. dd, J=llHz, 14Hz) 5. 95 (1H, dd, J=6Hz, 11Hz) 7.05(111, m) 7.14(1H, d, J=8Hz) 7.22-7.29(2H, m) 7. 47-7. 53 (2H, in) 7.60(1H, d, J=2Hz) 7.63-7.68(2H, m) 7.73-7.78(2H, m) 8.48(1H, d, J=5Hz) Preparative Fxample 23 N- ( 1 - f fi-f.hl oropvrl riin-2-vl )-?.-(pvrl rli n-2- - 60 - 27 21 vl t Pthvl Iphthal 1mi d<=» 38.6 g of the 1-(6-chloropyridin-2-yl)-2-(pyridin-2-yl)ethyl alcohol prepared' in the Preparative Example 20, "47.8 g of triphenylphosphine and 26.8 g of phthalimide were dissolved in 500 ml of tetrahydrofuran, followed by the addition thereto of 31.7 g of diethyl azodlcarboxylate. The obtained mixture was stirred at room temperature overnight and concentrated, followed by the addition thereto of diethyl ether. The obtained mixture was filtered to remove insolubles and the filtrate was purified by silica gel chromatography (with a hexane/ethyl acetate (2 : 1) mixture) to give 77.1 g of the title compound as a roughly purified product. - 61 - 272142 • ^-NMR (CDClj) 6 <PPm> 3.92(1H, dd, J=6Hz, 14Hz) 4.00(1H, dd, J=llHz, 14Hz) 6.04(1H, dd, j*6Hz, 11Hz) 7.04(1H, ddd, J=l, 5, 6Hz) 7.22(1H, d, J=8Hz) 7.33(1H, d, J=8Hz) 7.44-7.80(7H, m) 8.41(1H, ddd, J=l, 2, 5Hz) Prftparativfi Fxamplft 24 1 - ( R-Chl ornpvrl di n-2-vl ) -2 - (pvr 1 fi 1 n-2-vl ) fit.hvl amlns 1 8 of methanol was mixed with 77 g of the crude N-{1-(6-chloropyridin-2-yl)-2-(pyridin-2-yl)ethyl>-phthalimide prepared in the Preparative Example 23 and 16.5 g of hydrazine monohydrate. The obtained mixture was heated under reflux for 2 hours to conduct a reaction. After the reaction mixture was allowed to stand at room temperature, the precipitated crystals were filtered out and the filtrate was concentrated. Water and ethyl acetate were added to the concentrate to conduct extraction. The organic phase was washed with a saturated aqueous solution of common salt, dried over anhydrous sodium sulfate, and concentrated. 27 The residue was purified by silica gel chromatography (with a methanol/dichloromethane (5 : 95 mixture) to give 22.38 g of the title compound. • ^-NMR (CDC13) 6 (ppm) 3.09(1H, dd, J=9Hz, 14Hz) 3.26(1H, dd, J=5Hz, 14Hz) 4.48(1H, dd, J=5Hz, 9Hz) 7.09(1H, d, JK=8Hz) 7.13(1H, ddd, J=lHz, 5Hz, 8Hz) 7.19(1H, t, J=8Hz) 7.20(1H, t, J=8Hz) 7.56(1H, t, J=8Hz) 7.57(1H, td, J=8, 2Hz) 8.56(1H, ddd, J=l, 2, 5Hz) Prpparat.1 vp fvamplp 1 - (fl-Chl orophsnvl )-?.-(1 -tr Iphpnvl met.hvl iml riay.ol-9.-v1 ) ftt.hvl ami Tie The title compound was prepared in a similar manner to that of the Preparative Example 24. • te-NMR (CDCI3) 6 (ppm) 2.19(2H, d, J=7Hz) 3.94(1H, t, J=7Hz) 6.75(1H, /r-N NH2 CI I \ 1 - 63 - 27 d, J=2Hz) 6.83-6.86(1H, m) 6.90-6.93(1H, m) 6.99(1H, d, J=2Hz) 7.03-7.13(8H, m) 7.25-7.36(9H, m) Preparati vs Fxampls 2fi •fl - (4-Cal orr)pvr1d1n-2-vl ) - 2-(pvr 1 d i n -2-vl ) Iftthvl ami ns 99 g of the N-[{1-(4-chloropyridin-2-yl)-2-(pyridln-2-yl)}ethyl]phthalimlde prepared in the Preparative Example 21 was dissolved in 1 ( of ethanol, followed by the addition thereto of 41 ml of hydrazine monohydrate. The obtained mixture was refluxed for one hour. The precipitated white solid was filtered out and the filtrate was subjected to vacuum stripping. The residue was filtered to remove insolubles. The filtrate was purified by silica gel chromatography (with a chloroform/methanol (20 : 1) mixture) to give 38.6 g of the title compound as an oil. • ^-NMR (CDClj) 6 (ppm) - 64 - 272 2.26(2H, br-s) 3.07(1H, dd, J=9, 14Hz) 3.28(1H, dd, J = 5 , 14Hz) 4.50(1H, dd, J=5, 9Hz) 7.08(1H, d, J=8Hz) 7.14(1H, ddd, J-l, 5, 8Hz) 7.17(1H, dd. J=2, 5Hz) 7.34(1H, d, J=2Hz) 7.57(1H, td. J=8 , 2Hz) 8.47(1H, d, J = 6Hz) 8.57(1H, ddd,. J-l, 2, 5Hz) Prftparativp Frample 9.1 {1 -(4-Hhlornpvririln-2-vl 1-2-f pvri riln-2-vl )\-pthvlam1n ft (1) A solution of 2.5 g (15.5 mmol) of 1,1,1,3,3,3-hexamethyldisilazane in 6 ml of tetrahydrofuran was cooled to -20° C. 9.4 ml (15.5 mmol) of a 1.65 M solution of n-butyllithium in n-hexane was dropped into the resulting solution for 3 minutes in such a way that the temperature did not exceed -15°C. The obtained mixture was stirred at -20°C for 15 minutes. A solution of 2.0 g (14.1 mmol) of 4-chloro-2-pyridylaldehyde in 6 ml of tetrahydrofuran was dropped - 65 - 9 7 9 1 f- C> L t "ii into the resulting mixture for 3 minutes in such a way that the temperature did not exceed -15°C. The temperature of the mixture was raised to -10°C. The resulting: mixture was stirred for 15 minutes to give 2-(methyl-N-trimethylsilanylimino)-4-chloropyridine. (2) A solution of 1.6 g (17.2 mmol) of a-picoline in 60 ml of tetrahydrofuran was cooled to -65" C. 10.3 ml (17.0 mmol) of a 1.65 M solution of n-butylllthium in n-hexane was dropped into the solution for 3 minutes in such a way that the temperature did not exceed -55°C. The obtained solution was stirred at -65°C for 45 minutes. The 2-(methyl-N-trimethylsilanylimino)-4-chloropyridine prepared in the step (1) was dropped into the resulting solution for two minutes in such a way that the temperature did not exceed -60°C. The obtained mixture was stirred at -65°C for 15 minutes, diluted with 100 ml of a saturated aqueous solution of ammonium chloride, and extracted with 100 ml of ethyl acetate twice. The combined organic phases were dried over sodium sulfate and evaporated in a vacuum to dryness to give the title compound as a crude product. This crude product was purified by silica gel column chromatography (with a methanol/dichloromethane - 66 - system) to give the title compound as a green oil. Preparative Rxample 9ft 1 - ( 3-r.hl orophenvl ) - 2- (pvr 1 rlin-2-vl lethvl ami ne 150 ml of a solution of 5.25 g of hydrazine hydrate in ethanol was added to 12.7 g of the N-{l-(3-chlorophenyl)-2-(pyridin-2-yl)ethyl}phthalimide prepared in the Preparative Example 22. The obtained mixture was heated under reflux for 2 hours. The precipitated crystals were filtered out and the filtrate was concentrated, followed by the addition thereto of ethyl acetate. The precipitated impurities were filtered out and the filtrate was concentrated to give the title compound. Yield: 7.9 g. • ]H-NMR (CDOl 3) S (ppm) 3.01(1H, dd, J=9Hz, -14Hz) 3.11(1H, dd, J=5Hz, 14Hz) 4.48(1H, dd, J=5Hz, 9Hz) 7.05(1H, d, J=8Hz) 7.15(1H, ddd, J=2Hz, 5Hz, 8Hz) 7.18-7.27(3H, m) 7.41(1H, d, J=2Hz) 7.58(1H, td, J=2Hz, 8Hz) 8.58(1H, d, J=5Hz) - 67 - Prpnarat.Wp Fvampl e 29 f - ) -N- ■( 1 - f g . ri-r>1 -F1 iioronhpn vl T-2-(pvr1<1in-2-vl)lethvlamine A mixture comprising 36 g of {1-(2,5-difluoro-phenyl)-2-(pyridin-2-yl)}ethylamine, 25.73 g of R—(—)— mandelic acid, 32.43 g of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 22.86 g of 1-hydroxy-benzotriazole, 23.57 mg of triethylamine and 500 ml of tetrahydrofuran was heated under reflux for 45 minutes and cooled by allowing to stand, followed by the addition thereto of a saturated aqueous solution of sodium hydrogencarbonate and water in this order. The obtained mixture was extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and distilled in a vacuum to remove the solvent. The residue was subjected to silica gel chromatography and then to gradient elution with a chloroform/isopropyl alcohol (100 : 1 (v/v) to 50 : 1 (v/v)) mixture to recover the first eluted diastereomer, which was recrystallized from ethyl acetate/hexane to give 24.3 g of pure crystals. The crystals were added to 6 N hydrochloric acid and the obtained mixture was heated under reflux for 2 hours, basified with a IN aqueous solution of sodium hydroxide, and extracted with ethyl acetate. The - 68 - 27214 organic phase was washed with water, dried over anhydrous magnesium sulfate, and distilled in a vacuum to remove the solvent. Thus 13.1 g of the title compound was obtained. • [a]D20 = -55.9° (c = l, methanol) • ^i-NMR (CDC13) 6 (ppm) 3.03(1H, dd, J=14, 9Hz) 3.20(1H, dd, J=14, 5Hz) 4.72(1H, dd, J=9, 5Hz) 6.85-6.91(1H, m) 6.94-7.00(1H, m) 7.09(1H, d, J=8Hz) 7.13-7.21(2H, m) 7.58(1H, dt, J=8, 2Hz) 8.57(1H, ddd, J=5, 2, 1Hz) { + ) -N- f 1 - ( 9. . 5-TH-P1 linrnphpnvl )-?.-( pvrl ri1n-?-vl ) \ -pthvlamine • [a 1 d20 = +55-9# (c=l, methanol) Preparative Fyamplp 30 ( - ) -1 - f fi-r.hlnropvrl ri1n-?-v1 )-9- (pvr 1 H1n-9-v1 t -pthvlamine Tetrahydrofuran (1000 ml) was mixed with 22.4 g of (±)-1-(6-chlcropyridin-2-yl)-2-(pyridin-2-yl)-ethylamine, 14.6 g of (R)-(-)-mandelic acid, 20.3 g of - 69 - 2721 1-(3-dimethylamincpropyl)-3-ethylcarbodiimide hydrochloride, 16.1 g of 1-hydroxybenzotriazole and 16.6 ml of triethylamine. The obtained mixture was heated under reflux for one hour and the reaction mixture was concentrated, washed with water and a saturated aqueous solution of common salt, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography (with an isopropyl alcohol/chloroform (1 : 99) mixture). 15.2 g of the objective amine diastereomer was recovered as the first eluted fraction. 300 ml of 6N aqueous hydrochloric acid was added to the diastereomer (15.2 g). The obtained mixture was heated under reflux for 1.5 hours to conduct hydrolysis. The reaction mixture was cooled by allowing to stand, adjusted to pH13 with a dilute aqueous solution of sodium hydroxide, and extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of common salt, dried over anhydrous sodium sulfate, and concentrated to give 8.9 g of the title compound. • XH-NMR (CDCI3) 5 (ppm) 3.09(1H, dd, J=9Hz. 14Hz) 3.26(1H, dd , J=5Hz, 14Hz) 4.48(1H, dd, J=5Hz, 9Hz) 7.09(1H, d, J=8Hz) 7.13(1H, ddd, J=lHz, 5Hz, 8Hz) 7.19(1H, t, J=8Hz) 7.20(1H, t, J=8Hz) 7.56(1H, t, J=8Hz) - 70 - 2:2" *-2 7.57(1H, td. J=2Hz, 8Hz) 8.56(1H. ddd, J-lHz. 2Hz, 5Hz) Prpparat.1 vp fvampl p ( - 1 -1 - f 3-Chi orophenvl ^-9-fpvr1riin-?-v1 > pthvl ami tip 35.9 g of the .1-(3-chlorophenyl)-2-(pyridin-2-yl)ethylamine prepared in the Preparative Example 28 and 23.2 g of D-tartaric acid were dissolved in a mixture comprising 500 ml of ethanol and 100 ml of water at 90°C. The obtained solution was brought to room temperature and the precipitated crystals were recovered by filtration. The wet crystals thus obtained were dissolved in a mixture comprising 300 ml of ethanol and 60 ml of water at 90°C and the obtained solution was brought to room temperature. The crystals thus precipitated were recovered by filtration and suspended in an aqueous solution of sodium hydroxide. The obtained suspension was extracted with toluene. The toluene phase was dried - 71 - 27214 over magnesium sulfate and aistilled in a vacuum to remove the solvent, thus giving 7.7 g of the title compound as a pale-yellow oil. The optical purity of this product was determined by high-performance liquid chromatography (with a hexane/isopropanol (8 : 1) mixture containing 0.1% of diethylamine) (> 97 %ee). • tct]jj20 = -78.9° (c=0.598, methanol) • te-NMR (CDC13) 6 (ppm) 3.01(1H, dd, J=9Hz, 14Hz) 3.12(1H, dd, J=5Hz. 14Hz) 4.49(1H, dd, J=5Hz, 9Hz) 7.15(1H, dd, J=5Hz, 8Hz) 7.19-7.28(3H, m) 7.41(1H. s) 7.58(1H, td, J=2Hz, 8Hz) 7.60(1H, d, J=8Hz) 8 .59(1H, d, J = 5Hz) Preparative Fyample 32 f-> -n -f 4-r.hl ornpvri riin-2-vl )-?.-( nvri d in-2-vl ) \ -ethvlamine The title compound was prepared in a similar manner to that of the Preparative Example 30. - 72 - 2721 . LH-NMR (CDCI3) 5 (ppm) 3.07(1H, dd, J=9Hz, 14Hz) 3.28(1H, dd, J=5Hz, 14Hz) 4.50(1H, dd. J=5Hz, 9Hz) 7.08(1H, d, J=8Hz) 7.14(1H, dd. J=5Hz, 5Hz) 7.17(1H, d, J=5Hz) 7.34(1H, s) 7.57(1H, dd, J=5Hz, 5Hz) 8.47(1Hz, d, J=8Hz) 8.57(1H, J=5Hz) • [o]|)^ = -55.4° (c=0.386, methanol) (+)-{1-(4-Chloropyridin-2-yl)-2-(pyridin-2-yl))-ethylamine • [ a ] [j20 = +55.4° (c=0.386, methanol) Prsparfltinn Fxnmplp 33 ■4-Phenvl riazn'I P-S-rarhal r)f>hyrif> 1,4-Dioxane (10 ml) was mixed with 1 g of (4-phenyl-lH-imidazol-5-yl)methyl alcohol and 3 g of activated manganese dioxide. The obtained mixture was treated at 80°C for 30 minutes to conduct a reaction. The reaction mixture was passed through a hot filter and the filter cake was washed with acetone. The washings and the filtrate were combined and concentrated to give 0.7 g of the title compound. • XH-NMR (DMS0-d6) 5 (ppm) 73 v.7114 7.42-7.52(3H, m) 7.81-7.84(2H, m) 8.03(1H, s) 9.87(1H, s) Preparation Fxample 34 (FT-3-f 4-Phenyl -1H-imi da?n1 -n-vl t -?.-propenr>i r. arid hydrochloride 17.7 g of a 55% oily dispersion of sodium hydride was suspended in 500 ml of tetrahydrofuran, followed by the gradual addition thereto of a solution of 95 g of ethyl diethylphosplonoacetate in 200 ml of tetrahydrofuran. The obtained mixture was stirred as such at room temperature for 30 minutes, followed by the addition thereto of a solution of 63.6 g of 4-phenyl-lH-imidazole-5-carbaldehyde in 500 ml of tetrahydrofuran. The obtained mixture was stirred at room temperature overnight and concentrated, and water and ethyl acetate were added to the concentrate to conduct extraction. The organic phase was washed with a saturated aqueous solution of common salt, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography. - 74 - 2721*" Two main products were isolated by elution with a methanol/dichloromethane (2 : 98) mixture. Between the products, the first eluted one was ethyl ester of the objective compound. 21.5 g of the ester was obtained as a crude product. This crude product was dissolved in a mixture comprising 200 ml of methanol and a 2N aqueous solution of sodium hydroxide. The obtained solution was heated under reflux for one hour to conduct hydrolysis. The reaction mixture was concentrated, and water and dichloromethane were added to the concentrate to conduct extraction. The aqueous phase was washed with dichloromethane and adjusted to pH2 to 3 with hydrochloric acid. The precipitated crystals were recovered by filtration, washed with water, and dried to give 13.5 g of the title compound. • MS m/z: 215 (MH+) • ^-NMR (DMS0-d6) 5 (ppm) 6.15(1H, d, J=13Hz) 6.97(1H, d, J=13Hz) 7.53-7.67(5H, m) .9.13(1H, s) Preparation Example 35 ( 7.1 -3- f 4-Phf»nv1 -1 W-1 ml da?n"i -5-vl ) -9.-propp.noi o aolrl hvrlrorhl or1 rie - 75 - 1 k 9 COOH N^NH HC1 76.5 g of ethyl (Z)-3-(4-phenyl-lH-iraidazol-5-yl)-2-propenoate was obtained as another fraction of the silica gel chromatography conducted in the Example 29. This ester was dissolved in a mixture comprising 500 ml of methanol and a 2N aqueous solution of sodium hydroxide. The obtained solution was heated under reflux for one hour to conduct hydrolysis. The reaction mixture was concentrated, and water and dichloromethane were added to the concentrate to conduct extraction. The aqueous phase was washed with dichloromethane and adjusted to pH4 with hydrochloric acid. The precipitated crystals were recovered by filtration, washed with water, and dried to give 51.3 g of the title compound. • MS m/z: 215 (MH+) * ^-NMR (DMSO-d6) 6 (ppm) 6.90(1H, d, J=16Hz) 7.40(1H, d, J=16Hz) 7.54-7.65(6H, n) 9.40(1H, s) Prpnsration Fyampls n-(4-Chloropvr1riin-2-vl )-2-(pvri Hin-2-vl )>- - 76 - 2721 ethanrmo CI A solution of 1 g (11 mmol) of picoline in tetrahydrofuran (20 ml) was cooled to -78°C. 6.4 ml (11 mmol) of a 1.6 M solution of n-butyllithium in hexane was dropped into the solution, while the mixture was kept at a temperature of -60°C or below. After the completion of the dropping, the resulting mixture was stirred at that temperature for 30 minutes, followed by the addition thereto of a solution of 1.84 g (11 mmol) of methyl 4-chloro-picolinate in 40 ml of tetrahydrofuran which had been cooled to -40°C. The obtained mixture was stirred at that temperature for 30 minutes and brought to room temperature, followed by the addition thereto of 200 ml of ethyl acetate and 200 ml of water. The resulting mixture was neutralized with an aqueous solution of sodium hydrogencarbonate . The ethyl acetate phase was recovered, washed with water and an aqueous solution of common salt, dried over magnesium sulfate, and concentrated to give the title compound. - 77 - 27214 • ^-NMR (CDClg) keto form: enol form = 1 : 10 keto form: 5 (ppm) 4.70(10H, s) 7.17-7.34(10H, m) 7.48(10H, d, J=6Hz) 8.06(10H, s) 8.52-8.60(10H, m) enol form: 5 (ppm) 6.8K10H, S) 7.6K10H, dd, J=5, 6Hz) 7.20(10H, d. J=6Hz) 7.27(10H, d, J=5Hz) 7.67(10H. dd. J=5, 6Hz) 7.98(10H. s) 8.35(1H, d, J=5Hz) 8.5l(lH, d, J=5Hz) • MS m/z: 233 (MH+) Prpparatinn Example 37 11 -(4-r.hl oropvri ri1ri-2-v1 T-?.-fpvrirHn-9-v1 T \ -ethannng oxlme CI 50 ml of a methanolic solution of 1.4 g (22 mmol) of hydroxylaraine hydrochloride and 1.8 g (22 mmol) of sodium hydrogencarbonate was added to the 1-(4-chloro-2-pyridyl)-2-(2-pyridyl)ethanone prepared in the Example 31. The obtained mixture was stirred at room temperature for 18 hours and concentrated in a vacuum, followed by the addition thereto of 300 ml of 78 9 ' ? 1 A ■» GkSS* il J ethyl acetate and 200 ml of water. The resulting aqueous phase was adjusted to pH7 to recover the organic phase. The organic phase was washed with water and an aqueous solution of common salt, dried over magnesium sulfate, and concentrated in a vacuum. Acetone (20 ml) was added to the residue, and the precipitated crystals were recovered by filtration. 1.77 g of the title compound was obtained. Yield: 67%. • m.p. : 162-3° C • MS m/z: 248 (MH+) • elemental analysis as Cj^HjqCINjO C H N calcd.: 58.19 4.07 16.97% found: 58.29 4.10 16.83% • ^-NMR (CD30D) 6 (ppm) 4.70(2H, s) 7.17-7.24(2H, m) 7.35(1H, d, J=6Hz) 7.66(1H, dd, J=6, 6Hz) 8.00(1H, s) 8.34(1H, d, J=5Hz) 8.42(1H, d, J=5Hz) Preparation Example 38 11 - ( 4-r.hl ornpvri riin-2-vl 1-9- fpvri di n-2-vl ) Iftthvlamine - 79 - 2721* 15 g (60.6 mmol) of the 1-(4-chloro-2-pyridyl)-2-2-pyridyl)ethanone oxlme prepared in the Example 32 was dissolves in 120 ml of trifluoroacetic acid, followed by the addition thereto of 22 g of powdered zinc in several portions. After the completion of the addition, the reaction mixture was added to a mixture comprising 900 ml of a 2N aqueous solution of sodium hydroxide and 500 ml of dichloromethane under cooling with ice. The organic phase was recovered, washed with water and an aqueous solution of common salt, dried over magnesium sulfate, and concentrated in a vacuum to give 13.47 g of the title compound. Yield: 96%. Frample 1 f + l- fFI-M—H-f 3-Chi orophsnvl )-?.-(Pvr 1 rii n-2-vl 1 -ethvl >-3-f3-1 H-phenvl pvragol -4-vl ) - S-propenainl de - 80 - 2.93 g of (E)-(3-phenyl-lH-pyrazol-4-yl)-2-propenoic acid, 3.18 g of (-)-1-(3-chlorophenyl)-2-(pyridin-2-yl)ethylamine, 2.76 g of 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride, 1.94 g of 1-hydroxybenzotrlazole and 2.01 ml of triethylamlne were suspended in tetrahydrofuran. The obtained suspension was stirred at 60°C for one hour, followed by the addition thereto of water. The obtained mixture was extracted with ethyl acetate and the organic phase was dried over magnesium sulfate. The resulting mixture was freed from the magnesium sulfate by filtration and distilled in a vacuum to remove the solvent. The residue was purified by silica gel chromatography (with a dichloromethine/ethanol (20 : 1) mixture) to give 5.32 g of the title compound as a pale-yellow amorphous substance. * [alp20 = +76.6° (c = 0.483, methanol) • %-NMR (CDClg) 5 (ppm) - 81 - 272 f 3.18(1H, dd, J=8Hz, 14Hz) 3.32(1H, dd. J=5Hz, 14Hz) 5 .42(1H, m) 6.28C1H, d, J = 16Hz) 7.06(1H, d, J = 8Hz) 7.10-7.24(5H, m) 7.36-7.50(3H. m) 7.44-7.50(2H, m) 7.55(1H. d. J=16Hz) 7.58(1H. ■cd. J=2Hz , 8Hz) 7 . 80 (1H , s) 8.20(1H, d, J = 8Hz) 8.45(1H, d. J=5Hz) Exampl e .2 J+_.1 -.(F1 —N--I 1 - (4-Chl nrnpvri dl n-2-vl 1 -2- fpvri di n-9-vl lethvl >-3--f3-(3-fl uorophenvl 1-1 K-pvra7:ol-4-vl >-2-propsnamidp 7.1 g of (E)-{3-(3-fluorophenyl)-lH-pyrazol-4-yl}-2-propenoic acid, 6.5 g of (- )-1-(4-chloro-pyridin-2-yl)-2-(pyridin-2-yl)ethylamine, 5.9 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 4.1 g of 1-hydroxybenzotriazole and 4.3 ml of triethylamine were suspended in tetrahydrofuran. The obtained suspension was stirred at 60°C for one hour, followed by the addition thereto of water. The N H 82 2721 4 resulting mixture was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and the magnesium sulfate was filtered out. The filtrate was distilled in a vacuum to remove the solvent and the residue was purified by silica gel chromatography (with a dichloromethane/ethanol (20 : 1 to 10 : 1) mixture). The eluate was distilled in a vacuum to remove the solvent, thus giving a solid. Dichloromethine was added to the solid to form a gel, which was filtered to recover a solid. Dichloromethane was added to this solid to form a gel. This gel was filtered to give 5.22 g of the title compound as a white solid. * [c]D20 = +52.5° (c=0.594, methanol) • ^-NMR (CDC13) 5 (ppm) 3.34-3.46(2H, m) 5.55(1H. m) 6.30(1H, d, J = 16Hz) 7.04-7.20(5H, m) 7 . 20-7.30(2H, m) 7.38(1H, dt, J=6Hz, 9Hz) 7.56(1H, d, J=16Hz) 7.57(1H, dt, J=2Hz, 8Hz) 7.83(1H, s) 8.01(1H, d, J=8Hz) 8.41(1Hz, d, J=5Hz) 8.46(1H, d, J=5Hz) Fxamplpg 3 to 16 The title compounds were each prepared in a similar manner to that of the Example 1 or 2. Fxflmptp a - 83 - 2721 a? ((1 . 2-T)i phprivl pthvl ) -3- / 3- (th i ophen-?-v1 ) -1H-nvra7.ol-4-v1 \-2-proppnaTni Hp • iH-NMR (CDClg) 6 (ppm) 3.08-3.22(2H, m) 5.40(1H, td, J=8Hz, 8Hz) 6.14(1H, d, J=16Hz) 6.76(1H, d, J=8Hz) 6.86(1H, dd, J=3Hz, 5Hz) 7.04-7.28(12H, m) 7.47(1H, s) 7.61(1H, d, J=16Hz) Fvamplp A ( + )-(F)-N-f1 -(4-Chloropvrld1n-2-vl)-2-fpvrldln-2-vl 1 pthvl -3- ( 3-phpnvl -1 H-pvra7.nl -4-vl 1 -2-propgnaml rip H < \ . N H 84 /: a • ^-NMR (CDClg) « (ppm) 3.37(1H, dd. J=5Hz, 14Hz) 3.41(1H, dd. J=7Hz, 14Hz) 5.53-5.58(1H, m) 6.33(1H, d. J=16Hz) 7.10-7.14(3H, m) 7.20(1H, d, J=2Hz) 7.37-7.42(3H, m) 7.48-7.50(2H, m) 7.56(1H, dt, J=2Hz, 8Hz) 7.59(1H, d. J=16Hz) 7.82(1H, s) 8.13(1H. br) 8.38(1H, d. J=5Hz) 8.44(1H, ddd. J=lHz, 2Hz, 5Hz) Examp.1 r 5 ( -N-f 1 -( S-Chlormnhfinvl (pvrl d1 n-2- vl ) "Vpf.hvl -3--T 3- f 9.-<?hl orothl nphem-Fi-vl ) -TH-pvra7.nl -4-vl >-2-proppnain1 [a]D20 = +73.4° ^-NMR (CDClg) 5 (ppm) 3.18(1H. dd, J=9Hz, 14Hz) 3.33(1H, dd, J=4Hz, 14Hz) 5.45(1H. m) 6.26(1H, d, J=16Hz) 6.79(1H, - 85 - 27214,'! d. J=4Hz) 6.96(1H, d, J=4Hz) 7.12-7.26(6H, m) 7.55-7.63(2H, m) 7.68(1H, s) 8.44(1H, d, J=7Hz) 8.49(1H, ddd, J=lHz, 2Hz, 5Hz) Fyamplp fi ( + ) - (F~> -N--M - ( 9. 5-FHf 1 liorophpnvl > -2- (pvri din-2-vl)Ipthvl-3-f3-nhpnvl-1H-pvra?n1 -4-vl)-2-proppnami dp • ^-H-NMR (CDC13) 6 (ppm) 3.22(1H, dd, J=7Hz, 14Hz) 3.35(1H, dd, J=5Hz, 14Hz) 5.62-5.67(1H, m) 6.35(1H, d, J=16Hz) 6.95-7.02(2H, m) 7.17(1H, ddd, J=lHz, 5Hz, 8Hz) 7.40-7.61(7H, m) 7.91(1H, s) 8.02(1H, br-s) 8.50(1H, m) fFT -( 3- ( 2-r.hl nrnthi ophpn-5-vl T-1H-pvra7.nl -4-vl \-N-f1 -(pvrldin-2-vl)-2-phpnvl Ipt.hvl-2-propenami dp hvdrorhlori dp N H - 86 - • ^-NMR (DMSO-d6) 6 (ppm) 3.24(2H, m) 5.50(1H, m) 6.51(1H, d, J=16Hz) 7.13(1H, d. J=4Hz) 7.17(1H, d, J=4Hz) 7.20-7.37(5H, m) 7.41(1H, d, J=16Hz) 7.91(1H, m) 8.03(1H, d, J=8Hz) 8.17(1H, s) 8.52(1H, m) 8.84(1H, d, J=6Hz) 9.23(1H, m) Fvamplft 8 (- ( 3-Pbprivl -1H-pvra7.nl -4-vl ) -N- <1 . 2-rii (pvri rii rt-9-vl T pr.hvl-9-prnppnarni dp - 87 - 272143 • *H-NMR (CDClg) 6 (ppm) 3.37(1H, dd. J=6Hz, 14Hz) 3.43(1H. dd. J=8Hz, 14Hz) 5.60(1H, m) 6.33(1H, d, J=15Hz) 7 . 09-7.14(3H, m) 7.17(1H. d. J = 8Hz) 7.36-7.60(8H, m) 7.82(1H, s) 8.09(1H, d, J=8Hz) 8.44(1H, dd, J=2Hz, 5Hz) 8.48(1H, ddd, J=lHz, 2Hz, 5Hz) Example 9 (•+ 1 - fFT-N- -f 1 - < fi-Chl oropvri riin-2-vl T-2-fpvri din-3-vl Tpthvl -3-13-f3-f1norophpnvl ) -1 H-pvra 7n1 -4-vl 1-2-prnppnami rip • c a]D20 = +104.3° • ^-NMR (CDClg) 8 (ppm) 3.37(1H, dd, J=6Hz, 14Hz) 3.42(1H, dd, J=8Hz, 14Hz) 5.56(1H, m) 6.29(1H, d, J=16Hz) 7.02-7.37(8H, m) 7.49-7.58(2H, m) 7.77(1H, s) H CI 88 272142 8.01(1H, d. J=8Hz) 8.46(1H, dd, J=2Hz, 6Hz) Framplp 10 (FT - 3-f 3- ( ?.. Fi-r)1mpthv1fiiran-3-v1 ) -1 H-pvra 7.ol -4-v 1 l-N-f 1 - f 3-mpthoyvphenvl 1 -2- (pvr 1 rl 1 rt-2-vl 11 pthvl -2-prnppnamidp H • ^-NMR (CDCl-j) 5 (ppm) 2.25(3H, s) 2.26(3H, s) 3.20(1H, dd, J=8Hz, 14Hz) 3.34(1H, dd, J=5Hz, 14Hz) 3.73(3H, s) 5.42(1H, m) 6.01(1H, s) 6.22(1H, d, J=16Hz) 6.50-6.78(2H, m) 6.83(1H, d, J=8Hz) 7.05(1H, d, J=8Hz) 7.12-7.20(2H, m) 7.40(1H, d, J=16Hz) 7. 56(1H, td, J=2Hz, 8Hz) 7.75(1H, d, J=7Hz) 7.8K1H, S) 8 . 50 (1H , d, J=5Hz) Flxampl ft 11. (FT -3--T 3- ( 2-Chl orothlPhen-5-vl ) -!H-pvrfl7nl -4-vl 1 -N-{1 -(fnran-2-vl 1-2-phpnvl1pthvl-2-proDpnami dp - 89 - N H • !H-NMR (DMSO-dg) 8 (ppm) 3.02(1H, dd, J=7Hz, 14Hz) 3.13(1H, dd, J=5Hz. 14Hz) 5.23(1H, m) 6.23(1H, d, J=3Hz) 6.32-6.44(2H, m) 7.04-7.26(8H, m) 7.38(1H, d, J=16Hz) 7.57(1H, s) 8.16(1H, bs) 8.52(1H, d, J=9Hz) Fxampl (KT-N-M -Met.hvl -?.-phpnyl lethvl -3- f 3-phenvl -1H-pvra7.nl -4-vl T-P.-proppnami rip • %-NMR (DMSO-dg) 8 (ppm) 1.04(3H, d, J=6Hz) 2.63(1H, dd, J=7Hz, 13Hz) 2 . 79(1H, dd, J=7Hz , 13Hz) 4.05(1H, m) 6.35(1H, H - 90 - d, J=16Hz) 7.14-7.36(6H, m) 7.40-7.60(5H, m) 7.94(1H, d, J=8Hz) Fxrimplfi 13 (K) -3-f 3- r 2 . S-FHmethvl fnran-.?-v1 ) -1 H-pvrazol -4-vl >-NT-f 1 - ( 3-metl oxvphenvl )-2-( 9-methvlpvri di n-fi-vl ) -Pthvl\-2-propenamide • ^-NMR (CDC13) 5 (ppm) 2.23(3H, s) 2.24(3H, s) 2.51(3H. s) 3.13(1H, dd, J=8Hz, 14Hz) 3.28(1H, dd, J=5Hz, 14Hz) 3.73(3H, S) 5.39(1H, m) 6.01(1H, d, J=2Hz) 6.23C1H, d, J=16Hz) 6.72(1H, dd, J=3Hz, 8Hz) 6.78(IB, t, J=2Hz) 6.83(1H, d, J = 8Hz) 6.88(1H, d, J=8Hz) 7.00(1H, d, J=8Hz) 7.17(1H, t, J=8Hz) 7.41(1H, d, J=16Hz) 7.46(1H, t, J=8Hz) 7.80(1H, s) 8.04(1H, d, J=7Hz) Fxample 14 (F1 -NT- f 1 - ( S-f.hl orophsnvl )-2-(1 -tri phenvl methvl -imi darn!-2-vlT>ethv1 -3-f 3-(2-phi orothiophen-n-vl 1-1H- N' H CH3 - 91 - c/ £ -[&:LJ pvra7.o1 -4-vl l-P.-prnppnaml dp * to-NMR (CDClg) 5 (ppm) 2.32(1H, dd, J=4Hz, 16Hz) 2.68(1H, dd, J=8Hz, 16Hz) 4.32-4.40(1H, m) 6.10(1H, d, J=16Hz) 6.73(1H, s) 6.80(1H, d, J=4Hz) 6.88-7.14(11H, m) 7.25-7.35(9H, m) 7.53(1H, d. J=15Hz) 7.67(1H, s) 8.82(1H, d, J=8Hz) Fvamplfi 15 (K)-N-fl .2-D1 phpnvl p.thvl 1 - f 4-phpnvl -1H-1nrtda7,.r)1-5-vl)-2-proppnamldp - 92 - 2721 3.04(2H, d, J=8Hz) 5.28(1H, dd, J=7Hz, 15Hz) 6.40(1H, br-s) 6.98-7.30(16H, m) 7.56(1H, d, J=15Hz) Fvamnlp 1fi ( 7.1 -N- (1 . phpnvl Pthvl 1 - (4-phsnvl -1 TT-1m1 rtagol - ■S-vl )-?.-proppnam1 dp • ^-NMR (CDClg) 5 (ppm) 3.15(2H, d, J=8Hz) 5.32(1H, dd, J=8Hz, 15Hz) 5.51(1H, d. J=13Hz) 6.46(1H, d, J=8Hz) 6.82(1H, d, J=13Hz) 7.07-7•61(16H, br-s) Fvamplp 17 (FT-N--M -fS-Chlorophfinvl )-9.-f1H-iin1 clar.nl-2-vl ) )pthvl -3- na-f 2-rhl orothi nphpn-5-vl ) 1-1 H-pvrazol -4- - 93 - 2721 vl t-2-T)rnnpnami Hp H Trifluoroacetic acid (0.5 ml) was added to 10 ml of a dichloromethane solution of 0.25 g of the (E)-N-{1-(3-chloroplenyl)-2-(1-triphenylmethyl-imidazol-2-yl)}ethyl-3-{3-(2-chlorothiophen-5-yl)-1H-pyrazol-4-yl}-2-propenamide prepared in the Example 14 and the obtained mixture was stirred at room temperature overnight. Trifluoroacetic acid (0.5 ml) was added to the reaction mixture. The obtained mixture was stirred for 6 hours and distilled in a vacuum to remove most of the trifluoreacetic acid. The residue was subjected to silica gel column chromatography and then to gradient elution with a dichloromethane/methanol (80 : 1 to 70 : 1 (v/v)) mixture to give 0.126 g of the title compound. • ^-NMR (DMSO-dg) 5 (ppm) - 94 - 2721 A? 3.05-3.16(2H, m) 5.37(1H, q, J=8Hz) 6.47(1H, d, J=16Hz) 6.91(2H, S) 7.15-7.34(6H, m) 7.44(1H, d. J=16Hz) 8.2K1H, br-s) 8.80(1H, d. J=8Hz) 13.4(1H, br-s) Fvamplp 18 fFT -3--T ( 2-Chl nrnt.h 1 onhpn-5-vl >-1 H-pvra7.nl-4-vl \ -N2-phenvl-N2-banzyl-2-propenohvdrazide H 1.0 g of (E)-3-{3-(2-chlorothiophen-5-yI)-lH-pyrazol-4-yl}propenoic acid was dissolved in dichloromethane, followed by the addition thereto of 1.4 ml of oxalyl chloride and a catalytic amount of dimethylformamide. The obtained mixture was stirred at room temperature for 5 hours and distilled in a vacuum to remove the solvent and excess oxalyl chloride. The residue was dissolved in tetrahydrofuran, followed by the addition thereto of 1.6 ml of 2721*2 triethylamine and 940 mg of 1-phenyl-l-benzyl-hydrazine. The obtained mixture was stirred at room temperature for 30 minutes, followed by the addition thereto of water. The resulting mixture was extracted with ethyl acetate and the organic phase was dried over magnesium sulfate and distilled in a vacuum to remove the solvent. The residue was purified by silica gel column chromatography to give 620 mg of the title compound as a pale-yellow amorphous substance. • iH-NMR (DMSO-dg) 8 (ppm) 4.72(2H, S) 6.46(1H, d. J=16Hz) 6.70-6.81(3H, m) 7.10-7.4G(10H, m) 7.54(1H, d, J=16Hz) Example 19, ( + ) - fFV-N--T 1 - ( S-P.hl orophpnvl ) (Pvr 1 di n-2-vl ) -pthvl1-3-(1-rvanompthvl-3-phpnvl pvrazol-4-vl )-2-proppnainl dp 96 2721A° 19.1 g of (-)-(E)-N-{l-(3-chlorophenyl)-2-(pyridin-2-yl)ethyl}-3-(3-phenyl-lH-pyrazol-4-yl)-2-propenamide was dissolved in 150 ml of dimethyl-formamide, followed by the addition thereto of 2.73 g of 60% sodium hydride in portions under cooling with ice and stirring. The obtained mixture was stirred for 45 minutes, followed by the dropwise addition thereto of 4.76 ml of bromoacetonitrile. After 30 minutes, ice-water was added to the resulting mixture, followed by the extraction with ethyl acetate. The organic phase was dried over magnesium sulfate and the magnesium sulfate was filtered out. The filtrate was distilled in a vacuum to remove the solvent and the residue was purified by silica gel chromatography (with an ethyl acetate/n-hexane system). The first eluate was (+)-(E)-N-{l-(3-chlorophenyl)-2~(pyridin-2-yl)ethyl}-3-(2-cyanomethyl-3-phenylpyrazol-4-yl)-2-propenamide, which was crystallized from ethyl acetate/diethyl ether to give 3.34 g of a pale-yellow solid. The second eluate was the title compound, which was crystallized from ethanol/isopropyl ether to give 11.7 g of a white crystal. • [ a ] D20 = +44.5° ♦ *H-NMR (CDClg) 5 (ppm) 3.13(1H, dd, J = 7Hz, 14Hz) 3.33(1H, dd, J=5Hz, - 97 - 27? 1 "> 14Hz) 5.13(2H, s) 5.38(1H, m) 6.27(1H, d, J=16Hz) 6.95(1H, d, J=8Hz) 7.06(1H, m) 7.12-7.20(4H, m) 7.37-7.46(3H. m) 7.30-7.60(4H, m) 7.86(1H, s) 8.01(1H, d, J=7Hz) 8.50(1H, d, J=5Hz) Fxamnlpg 20 t.r> 9.R The following compounds were each prepared in a similar manner to that of the Example 19. Example 20 (-t- T - (F1 -3- (1 -nvanomsthvl -3-phpnvl pvrasol -4-vl )-N-I •? - ( 2 . 5-ri1 f lnorophenvl 1 - 2-f pvrl di ri-2-vl 1 ethvl -2-propftnaml tlft CN • m.p. : 175-176° C • MS m/z: 470 (MH+) • elemental analysis (as C27H21F2N5O) calcd.: C 69.08 H 4.51 N 14.92%. - 98 - 272 1 [«]D- found: C 69.10 H 4.56 N 14.88% D20 = +20.3° • ^-NMR (CDClg) 6 (ppm) 3.19(1H, dd. J=7Hz, 14Hz) 3.33(1H, dd, J=5Hz, 14Hz) 5.12(2H, s) 5.63(1H, dd. J»5Hz. 7Hz) 6.29(1H, d, J=16Hz) 6.63-6.67(1H, m) 6.79-6.85(1H, m) 6.94-7.00(2H, m) 7.l5(ddd, J=lHz, 5Hz, 5Hz) 7.36-7.58(6H, m) 7.87(1H, s) 8.05(1H, d, J=7Hz) 8.49(1H, ddd, J=lHz, 2Hz, 5Hz) Fxampl e> 9.1 ( + )- fFT -N-n - ( 2-r.hl nrnpvrl d1n-fi-v1 ) -2- (pvrl riln-?-vl ) sthvl 1-3-n -nvannmethvl -3- ( 3-f 1 norophenvl )pvra7.o1 -4-vl1-?-prnppnam1dp • [a ID20 = +75. 3° • ^H-NMR (CDC13) 6 (ppm) - 99 - 272142 3.31(1H, dd, J=6Hz, 14Hz) 3.43(1H, dd, J=7Hz, 14Hz ) 5 .13 (2H , s) 5.5M1H. dd , J=7Hz, 13Hz) 6.30(1H, d. J=16Hz) 7.00-7.16(5H. m) 7.26-7.56(6H, m) 7.71(1H, d, J=7Hz) 7.86(1H, s) 8.47(1H, m) Framplp 92 ()- (K) -N-f 1 - f 4-r,b1 oropvri di ri-2-yl 1 -9- (pvrl riin-2-vl )f>thv1-3-M-cvanompthvl ) -3-phpnvl pvrazol -4-vl ) )-2-prnpp-naTnl dp - ]H-NMR (CDC13) 6 (ppm) 3.33(1H, dd, J=5Hz, 14Hz) 3.43(1H, dd, J=7Hz, 14Hz) 5.12(2H, s) 5.51(1H, dd, J=5Hz, 7Hz) 6.30(1H, d, J=16Hz) 7.03(1H, d, J=7Hz) 7.10-7.15(3H, m) 7.40-7.59(6H, m) 7.84(1H, d, J=7Hz) 7.86(1H, s) 7.84(1H, d, J=7Hz) 7.86(1H, s) 8.41(1H, d, J=5Hz) 8.47(1H, ddd, J=lHz, 2Hz, 5:<iz) 100 27214 Example,,, 23. ( F1 -3- -fl -Cvanompthvl -3- ( 9 n-Hlmfithvl -fnran-3-vl ) -pvra?n1 -4-vl 1 -N- {1 - ( 3-msthnvvphpnvl )-?.-( ?-mfithv1 -pvri d i n-R-vl 1pthvl\-^-propfinamirip * :H-NMR (CDClg) & (ppm) 2.26(3H, s) 2,29(3H, s) 2.53(3H, s) 3.11(1H, dd, J=8Hz, 14Hz) 3.29(1H, dd, J=4Hz, 14Hz) 3.73(3H, s) 5.35(1H, m) 6.06(1H, s) 6.18(1H, d, J=16Hz) 6.70-6.74(2H, m) 6.77-6.82(2H, m) 7.00(1H, d, J=8Hz) 7.16(1H, m) 7.42(1H, d, J=16Hz) 7.43(1H, t, J=8Hz) 7.74(1H. s) 7.94(1H, d, J=7Hz) Fvampl p 9.4. (F1-3-f 1 -Cvarinmpthvl -3- ( 9.. 5-dimpthvl fnran-3-vl ) -pvra?nl -4-vl 1-N-M-f 3-mftthnxvphpnvl ) -9.- (Pvr 1 d1 n-?.-vl )>pthvl-2-propenam1dp N ci-I3 101 h3c /3-0CH3 O h3c CN • iH-NMR (CDClg) S (ppm) 2.27(3H, s) 2.30(3H, s) 3.17(1H, dd, J=8Hz, 14Hz) 3.33(1H, dd, J=5Hz, 14Hz) 3.72(3H, s) 5.0 5(2H, S) 5.39(1H, m) 6.06(1H, s) 6.20(1H, d, J=16Hz) 6.70-6.76(2H, m) 6.79(1H, d, J=8Hz) 7.00(1H, d. J=8Hz) 7.12-7.20(2H, m) 7.40(1H, d, J = 16Hz) 7 . 55(1H, td, J = 2Hz, 8Hz) 7.76(1H, s) 7.78(1H, d, J=8Hz) 8.51(1H. d, J=5Hz) Hxampl e 25. (FT - M -r.vanompt.hvl -3- ( 9. 5-d 1 nipthvl -Pnran-3-vl T -pvra7o1-4-v1 T -N- fl - ( 7.-m<>thv1 pvri din-fi-vl ) -9- (pvr 1 d 1 n-2-vl ) lethvl -P.-prnpgnanrt da 102 27214? h3c O h3c • %-NMR (CDClg) 5 (ppm) 2 . 27(3H, s) 2.31(3H, s) 2.52(3H, s) 3.28(1H, dd, J=6Hz, 14Hz) 3.42(1H, dd. J=7Hz, 14Hz) 5 . 08(2H, s) 5 . 49(1H, dd, J = 7Hz, 14Hz) 6.07(1H, s) 6.25(1H, d, J-18Hz) 6.81(1H, d, J=8Hz) 6 . 83(1H, d, J=8Hz) 7.05(1H, d, J=8Hz) 7.11(1H, in) 7.40(1H, m) 7.42(1H, d, J = 16Hz) 7.53(1H, td, J=2Hz, 8Hz) 7.67(1H, d, J=7Hz) 7.79(1H, s) 8.48(1H, m) Fyample 2fi ( + WF)-N-n - (3-r,hlorophe^v1 )-2-fpvr1 riin-7.-vl t lat.hvl - 3-11-rvannmpthvl-a- ( 2-rhl nrot.hl nphen-5-vl ) -pvra7.ol -4-vl >-2-proppnnm1 df> - 103 - CI 'CN • [G]d2" = +54.9° • !H-NMR (CDClg) S (ppm) 3.14(1H, dd, J=7Hz, 14Hz) 3.35(1H, dd, J=5Hz, 14Hz) 5.08(2H, s) 5.39(1H, m) 6.32(1H, d, J=16Hz) 6.88(1H, d. J=4Hz) 6.95(1H, d, J=8Hz) 7 -05-7.20(6H, m) 7.54-7.60(2H. m) 7.82(1H, s) 8.13(1H, d, J=6Hz) 8.55(1H, m) Flxampl.ft 27. (FT -3--M -nvannmsthvl -3- ( t.M ophf>n-2-v1 )pvra'/nl -4-v 1 y -M- f 1 • phenyl pthvl ) -2-propent.hi nainidfi - 104 - 27214? 720 mg of (E)-3-{1-cyanomethyl-3-(thiophen-2-yl)-pyrazol-4-yl}-N-(1,2-diphenylethyl)-2-propenamide and 2.2 g of Lawson's reagent were suspended in toluene. The obtained suspension was refluxed for 40 minutes and brought to room temperature. The precipitated solid was filtered out and the filtrate was distilled in a vacuum to remove the solvent. The residue was purified by silica gel chromatography to give 180 mg of the title compound as a pale-yellow amorphous substance. • ^-NMR (CDC13) 6 (ppm) 3.25(1H, dd, J=7Hz, 14Hz) 3.42(1H, dd , J=6Hz, 14Hz) 6.04(1H, td, J=7Hz, 7Hz) 6.57(1H, d, J=16Hz) 7.08-7.45(14H, m) 7.73(1H, s) 7.84(1H, d, J=16Hz) Exampl ft 28 The compound of Example 2 is obtained - 105 - 272H2 alternatively in the following manner. 4.0 g of (-)-[1-(4-chloro-pyridin-2-yl)-2-(pyridin-2-yl)]-ethylamine of Preparation Example 32 was dissolved in tetrahydrofurane under nirogen gas and then 4.2 g of (E)—[3-(3-fluorophenyl)-lH-pyrazol-4-yl]-2-propenoic acid and 3.6 g of 1—(3— dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added to the solution. It was stirred at 24°C for 19 hours. The reaction mixture was diluted with 120 ml of water and extracted with 240 ml of a 15% solution in methanol of ethyl acetate, and 40 ml of ethyl acetate. The two extract liquids were combined with each other and it was washed separately in order with 80 ml of a 1% aqueous acetic acid, 80 ml of a saturated solution of sodium hydrogencarbonate and 80 ml of a saturated salt water. It was concentrated and dried at a reduced pressure to obtain a crude product of the above titled compound having an HPLC purity of 98.1%. The product was dissolved in 120 ml of IN hydrochloric acid, washed'twice with 80 ml of dichloromethane and neutralized with sodium hydrogencarbonate. The precipitates were collected by filtration, washed well with water and dried in air at 50°C for 5 hours to obtain 17.25 g of the above titled compound with 95% yield, having an HPLC purity of t 106 - 2721A % 98.6%, being powder in light yellow. • = +52.5° (c=0.594, methanol) • ^-H-NMR (CDClj) 6 (ppm) 3 . 34-3.46(2H, m) 5.55(1H, m) 6.30(1H, d, J=16Hz) 7.04-7.20(5H, m) 7.20-7.30(2H. m) 7.38(1H, dt, J=6Hz, 9Hz) 7.56(1H. d, J=16Hz) 7.58(1H, dt, J=2Hz, 8Hz) 7.83(1H. s) 8.01(1H, d, J=8Hz) 8.41(1HZ, d. J=5Hz) 8.46(1H, d, J=5Hz) Fxiqmpl e 29 Monofumarate monohydrate of the compound of Example 2 38.0 g of the compound obtained by Example 2 was dissolved in 480 ml of ethanol and 160 ml of water, heated, and the insoluble was filtrated out. The liquid was stirred with ice and seeded. In 40 minutes, the precipitated crystals were collected by filtration and dried in air at 80°C for 2 days to obtain 39.0 g of the titled monofumarate monohydrate having a melting point of 153.5-156°C. • [a3d = +44.8° (c=l, methanol) • NMR (DMS0-a6, 6) 3.18(1H, dd J=14Hz, 9Hz) 3.32(1H, dd, J=14Hz, 5Hz) 5.43-5.50(1H, m) 6.44(1H, d, J=16Hz) 6.63(2H, S) 7.17-7.35(6H, m) 7.40-7.44(2H, m) - 107 - </div>

Claims

1. 272 14 P. 7.52-7.59(1H, ra) 7.66(1H, ddd, J=8Hz, 8Hz, 2Hz) 8.07(1H, bs) 8.48(1H, ddd, J=5Hz, 2Hz . 1Hz) 8.52(1H, dd, J=5Hz, 1Hz) 8.63(1H, d. J=8Hz) - 108 - 272142 WHAT WE CLAIM IS:

1. An amine represented by the following general formula (IV) 19 R r R20 (iv) h2N^^ wherein R19 and R20 may be the same or different from each other and each represents an optionally substituted aryl selected from phenyl and naphthyl; an optionally substituted arylalkyl selected from lower alkylphenyl and lower alkylnaphthyl; an optionally substituted heteroaryl selected from pyridyl, furanyl, thienyl, imidazolyl, triazolyl, oxazolyl, pyrazyl, pyrimidyl, pyridazinyl, thiazyl, isoxazolyl, benzimidazolyl, quinolyl, isoquinolyl and benzothiazolyl; or an optionally substituted heteroarylalkyl which is selected from an . optionally substituted heteroaryl as defined above being further substituted by lower alkyl, with the proviso that when R19 is 2-, 3- or 4-pyridyl, R20 does not represent phenyl and when R20 is 2-, 3- or 4-pyridyl, R19 does not represent phenyl.

An amine as claimed in claim 1, represented by the following formula: H?N

3. A compound as claimed in claim 1 as specifically set forth herein. [H Z- PATEMT OFFICE - 109 - 272142

4. A process for producing a compound as claimed in claim 1 substantially as herein described with reference to the Examples.

5. A compound as claimed in claim 2 as specifically set forth herein.

6. A process for producing a compound as claimed in claim 2 substantially as herein described with reference to the Examples. KTSAI CO.. LTD _ - Jy Its Attorneys BALDWIN, SON & CAREY